New chemical compounds

ABSTRACT

The present invention encompasses compounds of general formula (1) 
     
       
         
         
             
             
         
       
     
     wherein the groups R 1  to R 4 , Q a , Q b , Q H , L and n are defined as in claim  1 , which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, pharmaceutical preparations which contain such compounds and their use as medicaments.

The present invention relates to new quinoxaline, quinoline and quinazoline compounds of general formula (1)

wherein the groups R¹ to R⁴, Q^(a), Q^(b), Q^(H), L and n have the meanings given in the claims and specification, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, pharmaceutical preparations containing such compounds and their use as medicaments. The compounds according to the invention exhibit an inhibitory effect on the serine/threonine kinase PDK 1

BACKGROUND TO THE INVENTION

Quinazolines as PDK1 inhibitors are described for example in WO 2010/007114 and WO 2010/007116.

The aim of the present invention is to indicate new compounds which can be used for the prevention and/or treatment of diseases characterised by excessive or abnormal cell proliferation. The compounds according to the invention are characterised by a powerful inhibitory effect on PDK 1 and a high efficacy against tumour cells, e.g. prostate carcinoma cells, which is mediated through inhibiting PDK 1. As well as the inhibitory effect and cell potency the compounds have good solubility and good selectivity with regard to other signal and cell cycle kinases.

The importance of the PI3K-PDK1-AKT pathway with its frequent aberrations (PTEN loss, PI3K mutation) in the major tumor indications is described in numerous scientific publications (e.g. Samuels et al. 2004; Science; 304: 554; Samuels and Velculescu 2004; Cell cycle 3; 17-19; Samuels et al. 2005; Cancer Cell; 7: 561-573).

PDK1 alterations (mutations, CN gains) are rarely found isolated from other pathway alterations so that the importance of this target thrives from the fact that it acts as a central signaling node in a frequently altered pathway.

Active PI3K phosphorylates second messengers like Phosphatidylinositol(4.5)-bisphosphate (PtdIns(4.5)P₂) to PtdIns(3.4.5)P₃, or PtdIns(4)P to PtdIns(3.4,)P₂. Such PI3K products recruit AKT and PDK1 kinases via their PH-domains (which bind the PI3 kinase products) to the plasma membrane and allow PDK1 to phosphorylate Thr308 of AKT and thereby activate the enzyme. A second step important for additional AKT activation and/or AKT-substrate selection is mediated by the mTOR/rictor/SIN1 complex which phosphorylates the hydrophobic motif of AKT at Ser473. Activated AKT regulates several other proteins, which are involved in cell proliferation, growth and survival.

Besides AKT, PDK1 has other substrates located in the cytoplasm, e.g. p70S6K, p90RSK, PKCs and SGK, which are also implicated in regulating cell proliferation and cell survival. The activation of these kinases is not dependent on phosphatidylinositols in vitro and functions properly in cells where the PDK1-PH-domain had been destroyed by knock-in mutation (McManus et al. 2004, EMBO J. 23, 2071-2082). For a review on PDK1 mouse mutants also see Bayascas 2008; Cell cycle 7; 2978-2982).

In conclusion, PDK1 substrates (AKT, p90RSK) act at the crossroad of two important cancer signaling pathways.

A potent and selective inhibitor of the PDK1 kinase is predicted to inhibit tumor growth, delay relapse, or even induce objective tumor responses (i.e. complete or partial tumor shrinkage) in cancer patients.

DETAILED DESCRIPTION OF THE INVENTION

It has been found that, surprisingly, compounds of general formula (1) wherein the groups R¹ to R⁴, Q^(a), Q^(b), Q^(H), L and n are defined as stated hereinafter act as inhibitors of specific signal enzymes which are involved in controlling the proliferation of cells. Thus, the compounds according to the invention may be used for example for the treatment of diseases which are connected with the activity of these signal enzymes and are characterised by excessive or abnormal cell proliferation.

The present invention therefore relates to compounds of general formula (1)

wherein

(A0)

Q^(a) is a ring system optionally substituted by one or more identical or different R^(a) and/or R^(b), selected from among C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl;

(B0)

R¹ and R² are selected independently of one another from among hydrogen, halogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄haloalkyl, —NH₂, —CN, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)₂, —OH, —OC₁₋₄alkyl, HO—C₁₋₄alkylene, C₁₋₄alkyl-O—C₁₋₄alkylene, H₂N—C₁₋₄alkylene, —OC₁₋₄haloalkyl, (C₁₋₄alkyl)NH—C₁₋₄alkylene- and (C₁₋₄alkyl)₂N—C₁₋₄alkylene, while alkyl, alkenyl, alkynyl and alkylene mentioned in the above groups may optionally be substituted by one or more identical or different halogens;

(C0)

the ring system Q^(b) is selected from among

each R³ is independently selected from among halogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄haloalkyl, —NH₂, —CN, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)₂, —OH, —OC₁₋₄alkyl, HO—C₁₋₄alkylene, HO—C₂₋₄alkylene-O, C₁₋₄alkyl-O—C₁₋₄alkylene, C₁₋₄haloalkyl-O—C₁₋₄alkylene, H₂N—C₁₋₄alkylene, C₁₋₄alkyl-O—C₂₋₄alkylene-O, (C₁₋₄alkyl)NH—C₁₋₄alkylene, (C₁₋₄alkyl)₂N—C₁₋₄alkylene, —OC₁₋₄haloalkyl, H₂N—C₂₋₄alkylene-O—, —NH(C₂₋₄alkylene-NH₂), —NH[C₂₋₄alkylene-N(HC₁₋₄alkyl)], —NH[C₂₋₄alkylene-N(C₁₋₄alkyl)₂], (C₁₋₄alkyl)₂N—C₂₋₄alkylene-O—, (C₁₋₄haloalkyl)₂N—C₂₋₄alkylene-O—, (C₁₋₄haloalkyl)NH—C₂₋₄alkylene-O— and (C₁₋₄alkyl)NH—C₂₋₄alkylene-O—; n denotes the number 0, 1, 2 or 3 if Q^(b) corresponds to the ring system Q^(b)-4; each n independently denotes the number 0, 1 or 2 if Q^(b) corresponds to one of the ring systems Q^(b)-1, Q^(b)-2, Q^(b)-3 or Q^(b)-5;

-   -   while a group R³ in the ring systems Q^(b)-1 to Q^(b)-5 in each         case replaces a hydrogen;

(D0)

R⁴ denotes hydrogen or C₁₋₄alkyl;

(E0)

L denotes the group

and in the latter case the groups —CR⁵R⁶— and Q^(H) may assume both a cis and a trans configuration with respect to the double bond; R⁵ and R⁶ are each independently of one another selected from among hydrogen, halogen, C₁₋₄alkyl, C₁₋₄haloalkyl;

(F0)

the ring system Q^(H) is selected from among

R⁷ and R⁹ are each independently of one another selected from among hydrogen, halogen, —NR^(a)R^(a), —N(OR^(a))R^(a), —OR^(a), —COOR^(a), —COR^(a), —CONR^(a)R^(a), —SR^(a), —NO₂ and —CN or denote a group optionally substituted by one or more identical or different R^(b) and/or R^(c), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; R⁸ is independently selected from among hydrogen, —NR^(a)R^(a), —N(OR^(a))R^(a), —OR^(a), —COOR^(a), —COR^(a), —CONR^(a)R^(a) and —SR^(a) or denotes a group optionally substituted by one or more identical or different R^(b) and/or R^(c), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; R¹⁰ is independently selected from among —NR^(a)R^(a), —N(OR^(a))R^(a), —OR^(a) and —SR^(a) or denotes a group optionally substituted by one or more identical or different R^(b) and/or R^(c) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl;

(G0)

each R¹¹ and R¹² is independently selected from among R^(a) and R^(b); m denotes the number 0, 1 or 2; each R^(a) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(b) and/or R^(c), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(b) is independently selected from among —OR^(c), —NR^(c)R^(c), halogen, —CN, —NO₂, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c), —S(O)₂R^(c), —S(O)₂NR^(c)R^(c), —NHC(O)R^(c) and —N(C₁₋₄alkyl)C(O)R^(c) as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(c) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d) and/or R^(e), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(d) is independently selected from among —OR^(e), —NR^(e)R^(e), halogen, —CN, —NO₂, —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(e)R^(e), —S(O)₂R^(e), —S(O)₂NR^(e)R^(e), —NHC(O)R^(e) and —N(C₁₋₄alkyl)C(O)R^(e), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(e) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(f) and/or R^(g), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(f) is independently selected from among —OR^(g), —NR^(g)R^(g), halogen, —CN, —NO₂, —C(O)R^(g), —C(O)OR^(g), —C(O)NR^(g)R^(g), —S(O)₂R^(g), —S(O)₂NR^(g)R^(g), —NHC(O)R^(g) and —N(C₁₋₄alkyl)C(O)R^(g), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems and each R^(g) is independently selected from among hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl and the above-mentioned groups R^(g) may optionally be substituted by one or more identical or different substituents, selected independently of one another from among —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂ and C₁₋₆alkyl; while the compounds (1) may optionally also be present in the form of the tautomers, racemates, enantiomers, diastereomers or mixtures thereof or as the respective salts of all the above-mentioned forms.

In one aspect (A1) the invention relates to compounds (1), wherein

Q^(a) is a ring system optionally substituted by one or more identical or different R^(a) and/or R^(b) selected from among C₅₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl and 5-7 membered heterocyclyl, and R^(a) and R^(b) are as hereinbefore defined.

In another aspect (A2) the invention relates to compounds (1), wherein Q^(a) is a ring system optionally substituted by one or more identical or different R^(a) and/or R^(b) selected from among phenyl and 5-6 membered heteroaryl, and

R^(a) and R^(b) are as hereinbefore defined.

In other aspects (A3)(A4) the invention relates to compounds with a structural aspect (A1) and (A2), wherein the ring system Q^(a) optionally carries one or more identical or different substituents, selected from among halogen and C₁₋₄alkyl.

In another aspect (A5) the invention relates to compounds (1) wherein

Q^(a) is selected from among phenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4,5-trifluorophenyl, 3,5-difluorophenyl and 3,4-difluorophenyl.

In another aspect (A6) the invention relates to compounds (1) wherein

Q^(a) denotes 3,4-difluorophenyl.

In another aspect (B1) the invention relates to compounds (1) wherein

R¹ and R² are selected independently of one another from among hydrogen, C₁₋₄alkyl, C₂₋₄alkynyl, —CN, HO—C₁₋₄alkylene-, H₂N—C₁₋₄alkylene-, (C₁₋₄alkyl)NH—C₁₋₄alkylene-, (C₁₋₄halolkyl)NH—C₁₋₄alkylene-, (C₁₋₄alkyl)₂N—C₁₋₄alkylene- and (C₁₋₄haloalkyl)₂N—C₁₋₄alkylene-.

In another aspect (B2) the invention relates to compounds (1), wherein

R¹ and R² are selected independently of one another from among hydrogen, C₁₋₄alkyl, H₂N—C₁₋₄alkylene and HO—C₁₋₄alkylene.

In another aspect (B3) the invention relates to compounds (1), wherein

R¹ and R² are independently selected from among hydrogen, methyl, aminomethyl and hydroxymethyl.

In further aspects (B4)(B5)(B6) the invention relates to compounds with a structural aspect (B1), (B2) and (B3), wherein

R¹ denotes hydrogen.

In another aspect (C1) the invention relates to compounds (1), wherein the ring system Q^(b) is selected from among

each R³ is independently selected from among halogen, C₁₋₄alkyl, —OC₁₋₄alkyl, HO—C₁₋₄alkylene, C₁₋₄alkyl-O—C₁₋₄alkylene, —NH(C₂₋₄alkylene-NH₂), —NH[C₂₋₄alkylene-NH(C₁₋₄alkyl)] and —NH[C₂₋₄alkylene-N(C₁₋₄alkyl)₂]; n denotes the number 0, 1, 2 or 3 if Q^(b) corresponds to the ring system Q^(b)-4 and each n independently denotes the number 0, 1 or 2 if Q^(b) corresponds to one of the ring systems Q^(b)-1, Q^(b)-2, Q^(b)-3 or Q^(b)-5,

-   -   while a group R³ in the ring systems Q^(b)-1 to Q^(b)-5 in each         case replaces a hydrogen.

In another aspect (C2) the invention relates to compounds (1), wherein the ring system Q^(b) is selected from among

and n has the value 0.

In another aspect (C3) the invention relates to compounds (1), wherein

the ring system Q^(b) is selected from among

and n has the value 0.

In another aspect (C4) the invention relates to compounds (1), wherein

the ring system Q^(b) together with the n substituents R³ is selected from among

In another aspect (D1) the invention relates to compounds (1), wherein

R⁴ denotes hydrogen or methyl.

In another aspect (D2) the invention relates to compounds (1), wherein

R⁴ denotes hydrogen.

In another aspect (E1) the invention relates to compounds (1), wherein

L denotes the group

In another aspect (F1) the invention relates to compounds (1), wherein

the ring system Q^(H) is selected from among

R⁷ is independently selected from among hydrogen, —NR^(a)R^(a), —N(OR^(a))R^(a), —OR^(a), —COOR^(a), —COR^(a), —CONR^(a)R^(a) and —SR^(a), or denotes optionally substituted by one or more identical or different R^(b) and/or R^(c), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, and R¹¹, R¹², R^(a), R^(b), R^(c) and m are as hereinbefore defined.

In another aspect (F2) the invention relates to compounds (1), wherein

the ring system Q^(H) is selected from among

R⁷ is independently selected from among hydrogen, —NR^(a1)R^(a1), —N(OR^(a1))R^(a1), —OR^(a1), —COOR^(a1), —COR^(a1), —CONR^(a1)R^(a1) and —SR^(a1) or denotes a group optionally substituted by one or more identical or different R^(b1) and/or R^(c1) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(a1) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(b1) and/or R^(c1) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-14 membered heterocyclyl; each R^(b1) is independently selected from among —OR^(c1), —NR^(c1)R^(c1) and halogen; each R^(c1) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d1) and/or R^(e1) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-14 membered heterocyclyl; each R^(d1) is independently selected from among —OR^(e1), —CN and —C(O)OR^(e1); each R^(e1) independently denotes hydrogen or a group optionally substituted by one or more identical or different cycloalkyl (particularly C₃₋₆cycloalkyl) selected from among C₁₋₆alkyl and C₃₋₁₀cycloalkyl, and R¹¹, R¹² and m are as hereinbefore defined.

In another aspect (F3) the invention relates to compounds (1), wherein

the ring system Q^(H) denotes

R⁷ is selected from among hydrogen, —NR^(a1)R^(a1), —OR^(a1) and —SR^(a1), or denotes a group optionally substituted by one or more identical or different R^(b1) and/or R^(c1), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, homomorpholinyl, azetidinyl and homopiperazinyl; each R^(a1) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(b1) and/or R^(c1), selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl and pyrrolidinyl; each R^(b1) is independently selected from among —OR^(c1), —NR^(c1)R^(c1) and halogen; each R^(c1) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d1) and/or R^(e1) selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl, pyrrolidinyl, morpholinyl, homomorpholinyl, piperazinyl, homopiperazinyl, oxetanyl and piperidinyl; each R^(d1) is independently selected from among —OR^(e1), —CN and —C(O)OR^(e1); each R^(e1) independently denotes hydrogen or a group optionally substituted by one or more identical or different C₃₋₆cycloalkyl, selected from among C₁₋₆alkyl and C₃₋₆cycloalkyl, and R¹¹ and m are as hereinbefore defined.

In another aspect (F4) the invention relates to compounds (1), wherein

the ring system Q^(H) denotes

R⁷ denotes —NHR^(a1), R^(a1) is a group optionally substituted by one or more identical or different R^(b1) and/or R^(c1), selected from among C₁₋₄alkyl, cyclohexyl, cyclopentyl and piperidinyl; each R^(b1) is independently selected from among —NR^(c1)R^(c1) and fluorine; each R^(c1) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d1) and/or R^(e1), selected from among C₁₋₄alkyl, cyclopropyl, morpholinyl, piperazinyl and oxetanyl; each R^(d1) denotes —OR^(e1); each R^(e1) independently denotes hydrogen or a C₁₋₄alkyl optionally substituted by cyclopropyl, and R¹¹ and m are as hereinbefore defined.

In another aspect (F5) the invention relates to compounds (1), wherein

the ring system Q^(H) denotes

R⁷ is selected from among

and R¹¹ and m are as hereinbefore defined.

In another aspect (F6) the invention relates to compounds (1), wherein

the ring system Q^(H) is selected from among

R⁹ is independently selected from among hydrogen, —NR^(a)R^(a), —N(OR^(a))R^(a), —OR^(a), —COOR^(a), —COR^(a), —CONR^(a)R^(a) and —SR^(a), or denotes a group optionally substituted by one or more identical or different R^(b) and/or R^(c), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, and R¹¹, R¹², R^(a), R^(b), R^(c) and m are as hereinbefore defined.

In another aspect (F7) the invention relates to compounds (1), wherein

the ring system Q^(H) is selected from among

R⁹ is independently selected from among hydrogen, —NR^(a2)R^(a2), —N(OR^(a2))R^(a2), —OR^(a2), —COOR^(a2), —COR^(a2), —CONR^(a2)R^(a2) and —SR^(a2), or denotes a group optionally substituted by one or more identical or different R^(b2) and/or R^(c2), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(a2) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(b2) and/or R^(c2) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-14 membered heterocyclyl; each R^(b2) is independently selected from among —OR^(c2), —NR^(c2)R^(c2) and halogen; each R^(b2) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d2) and/or R^(e2) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-14 membered heterocyclyl; each R^(d2) is independently selected from among —OR^(e2), —CN and —C(O)OR^(e2); each R^(e2) independently denotes hydrogen or a group optionally substituted by one or more identical or different cycloalkyl (particularly C₃₋₆cycloalkyl) selected from among C₁₋₆alkyl and C₃₋₁₀cycloalkyl, and R¹¹, R¹² and m are as hereinbefore defined.

In another aspect (F8) the invention relates to compounds (1), wherein

the ring system Q^(H) denotes

R⁹ is selected from among hydrogen, —NR^(a2)R^(a2), —OR^(a2) and —SR^(a2), or denotes a group optionally substituted by one or more identical or different R^(b2) and/or R^(c2) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, homomorpholinyl, azetidinyl and homopiperazinyl; each R^(a2) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(b2) and/or R^(c2), selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl and pyrrolidinyl; each R^(b2) is independently selected from among —OR^(c2), —NR^(c2)R^(c2) and halogen; each R^(c2) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d2) and/or R^(e2), selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl, pyrrolidinyl, morpholinyl, homomorpholinyl, piperazinyl, homopiperazinyl, oxetanyl and piperidinyl; each R^(d2) is independently selected from among —OR^(e2), —CN and —C(O)OR^(e2); each R^(e2) independently denotes hydrogen or a group optionally substituted by one or more identical or different C₃₋₆cycloalkyl, selected from among C₁₋₆alkyl and C₃₋₆cycloalkyl, and R¹¹ and m are as hereinbefore defined.

In another aspect (F9) the invention relates to compounds (1), wherein

the ring system Q^(H) denotes

R⁹ denotes —NHR^(a2); R^(a2) is a group optionally substituted by one or more identical or different R^(b2) and/or R^(c2) selected from among C₁₋₄alkyl, cyclohexyl, cyclopentyl and piperidinyl; each R^(b2) is independently selected from among —NR^(c2)R^(c2) and fluorine; each R^(c2) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d2) and/or R^(e2), selected from among C₁₋₄alkyl, cyclopropyl, morpholinyl, piperazinyl and oxetanyl; each R^(d2) denotes —OR^(e2); each R^(e2) independently denotes hydrogen or a C₁₋₄alkyl optionally substituted by cyclopropyl, and R¹¹ and m are as hereinbefore defined.

In another aspect (F10) the invention relates to compounds (1), wherein

the ring system Q^(H) denotes

R⁹ is selected from among

and R¹¹ and m are as hereinbefore defined.

In another aspect (F11) the invention relates to compounds (1), wherein

the ring system Q^(H) is selected from among

R⁸ is selected from among hydrogen, —NR^(a)R^(a), —N(OR^(a))R^(a), —OR^(a) and —SR^(a), or denotes a group optionally substituted by one or more identical or different R^(b) and/or R^(c), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; R⁹ is independently selected from among hydrogen, halogen, —NO₂, —CN and C₁₋₄alkyl, and R¹¹, R¹², R^(a), R^(b), R^(c) and m are as hereinbefore defined.

In another aspect (F12) the invention relates to compounds (1), wherein

the ring system Q^(H) is selected from among

R⁸ is selected from among —NR^(a3)R^(a3) and —OR^(a3), or denotes a group optionally substituted by one or more identical or different R^(b3) and/or R^(c3) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; R⁹ is independently selected from among hydrogen, halogen, —NO₂, —CN and C₁₋₄alkyl; each R^(a3) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(b3) and/or R^(c3) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl and 3-14 membered heterocyclyl; each R^(b3) is independently selected from among —OR^(c3) and —NR^(c3)R^(c3); each R^(c3) independently denotes hydrogen or a group optionally substituted by one or more identical or different C₁₋₆alkyl selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl and 3-14 membered heterocyclyl, and R¹¹, R¹² and m are as hereinbefore defined.

In another aspect (F13) the invention relates to compounds (1), wherein

the ring system Q^(H) denotes

R⁸ is selected from among —NR^(a3)R^(a3) and —OR^(a3), or denotes a group optionally substituted by one or more identical or different R^(b3) and/or R^(c3), selected from among C₁₋₆alkyl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl; R⁹ is independently selected from among hydrogen, halogen, —NO₂, —CN and C₁₋₄alkyl; each R^(a3) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(b3) and/or R^(c3), selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl, pyrrolidinyl, and piperidinyl; each R^(b3) is independently selected from among —OR^(c3) and —NR^(c3)R^(c3); each R^(c3) independently denotes hydrogen or a group optionally substituted by one or more identical or different C₁₋₆alkyl, selected from among C₁₋₆alkyl, piperazinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuryl and pyrrolidinyl, and R¹¹ and m are as hereinbefore defined.

In another aspect (F14) the invention relates to compounds (1), wherein

the ring system Q^(H) denotes

R⁸ denotes —OR^(a3); R⁹ is independently selected from among hydrogen, halogen, —NO₂, —CN and C₁₋₄alkyl; R^(a3) denotes a C₁₋₆alkyl which is substituted by a substituent selected from among —N(C₁₋₄alkyl)₂, piperidinyl, piperazinyl or pyrrolidine, while the above-mentioned piperidinyl, piperazinyl and pyrrolidine may optionally be substituted by a C₁₋₄alkyl and R¹¹ and m are as hereinbefore defined.

In another aspect (F15) the invention relates to compounds (1), wherein

the ring system Q^(H) denotes

R⁸ is selected from among

R⁹ is independently selected from among hydrogen, halogen, —NO₂, —CN and C₁₋₄alkyl, and R¹¹ and m are as hereinbefore defined.

In another aspect (F16) the invention relates to compounds (1), wherein

the ring system Q^(H) is selected from among

R¹⁰ is independently selected from among —NR^(a)R^(a), —N(OR^(a))R^(a), —OR^(a) and —SR^(a) or denotes a group optionally substituted by one or more identical or different R^(b) and/or R^(c) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, and R¹¹, R¹², R^(a), R^(b), R^(c) and m are as hereinbefore defined.

In another aspect (F17) the invention relates to compounds (1), wherein

the ring system Q^(H) is selected from among

R¹⁰ is independently selected from among —NR^(a4)R^(a4), —N(OR^(a4))R^(a4), —OR^(a4) and —SR^(a4) or denotes a group optionally substituted by one or more identical or different R^(b4) and/or R^(c4) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(a4) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(b4) and/or R^(c4) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl and 3-14 membered heterocyclyl; each R^(b4) is independently selected from among —OR^(c4), —NR^(c4)R^(c4), —C(O)R^(c4), —C(O)OR^(c4), —C(O)NR^(c4)R^(c4), —NHC(O)R^(c4) and —N(C₁₋₄alkyl)C(O)R^(c4); each R^(c4) independently of one another denotes hydrogen or a group optionally substituted by one or more identical or different R^(d4) and/or R^(e4), selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(d4) denotes —OR^(e1); each R^(e4) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(f4) selected from among C₁₋₆alkyl and C₆₋₁₀aryl; each R^(f4) denotes halogen and R¹¹, R¹² and m are as hereinbefore defined.

In another aspect (F18) the invention relates to compounds (1), wherein

the ring system Q^(H) denotes

R¹⁰ is selected from among —NR^(a4)R^(a4), —N(OR^(a4))R^(a4) and —OR^(a4) or denotes a group optionally substituted by one or more identical or different R^(b4) and/or R^(c4) selected from among C₁₋₆alkyl, phenyl, 5-6 membered heteroaryl, piperazinyl, pyrrolidinyl, morpholinyl, homomorpholinyl, homopiperazinyl and piperidinyl;

each R^(a4) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(b4) and/or R^(c4) selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl, azetidinyl, tetrahydropyranyl, piperidinyl and pyrrolidinyl; each R^(b4) is independently selected from among —OR^(c4), —NR^(c4)R^(c4), —C(O)R^(c4), —C(O)OR^(c4), —C(O)NR^(c4)R^(c4) and —NHC(O)R^(c4); each R^(c4) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d4) and/or R^(e4) selected from among C₁₋₆alkyl, phenyl, furyl, pyridyl, imidazolyl, thienyl, pyrazolyl, quinolinyl, oxetanyl, tetrahydrofuryl, azetidinyl, pyrrolidinyl, piperidinyl and piperazinyl; each R^(d4) denotes —OR^(e4); each R^(e4) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(f4) selected from among C₁₋₆alkyl and phenyl; each R^(f4) denotes halogen and R¹¹ and m are as hereinbefore defined.

In another aspect (F19) the invention relates to compounds (1), wherein

the ring system Q^(H) denotes

R¹⁰ is selected from among —NHMe, —NMe₂ and —NEt₂, and

R¹¹ and m are as hereinbefore defined.

In another aspect (G1) the invention relates to compounds (1), wherein

each R¹¹ and R¹² is independently selected from among hydrogen, C₁₋₄alkyl and halogen, and m denotes the value 0, 1 or 2.

In another aspect (G2) the invention relates to compounds (1), wherein each R¹¹ and R¹² is independently selected from among hydrogen, C₁₋₄alkyl and halogen, and

m denotes the value 0 or 1.

In another aspect (G3) the invention relates to compounds (1), wherein

m has the value 0.

All the above-mentioned structural aspects A1 to A6, B1 to B6, C1 to C4, D1 and D2, E1, F1 to F19 and G1 to G3 are preferred embodiments of the aspects A0, B0, C0, D0, E0, F0 and G0, respectively. The structural aspects A0 to A6, B0 to B6, C0 to C4, D0 to D2, E0 and E1, F0 to F19 and G0 to G3 relating to different molecular parts of the compounds (1) according to the invention may be permutated with one another as desired in combinations ABCDEFG so as to obtain preferred compounds (1). Each combination ABCDEFG represents and defines individual embodiments or generic amounts of compounds A0B0C0D0E0F0G0 according to the invention. Each individual embodiment or partial quantity defined by this combination is expressly also included and is a subject of the invention.

The present invention further relates to all the pharmaceutically acceptable salts of compounds of general formula (1).

The present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives and prodrugs of compounds of general formula (1).

In another aspect the invention relates to compounds of general formula (1)—or the pharmaceutically acceptable salts thereof—as medicaments.

In another aspect the invention relates to compounds of general formula (1)—or the pharmaceutically acceptable salts thereof—for use in the treatment and/or prevention of cancer, infections, inflammations and autoimmune diseases.

In another aspect the invention relates to compounds of general formula (1)—or the pharmaceutically acceptable salts thereof—for use in the treatment and/or prevention of cancer.

In another aspect the invention relates to compounds of general formula (1)—or the pharmaceutically acceptable salts thereof—for use in the treatment and/or prevention of carcinomas of the breast, prostate or ovary, non-small-cell bronchial carcinomas (NSCLC), melanomas and chronic lymphatic leukaemias (CLL).

In another aspect the invention relates to a process for the treatment and/or prevention of cancer comprising administering a therapeutically effective amount of a compound of general formula (1)—or one of the pharmaceutically acceptable salts thereof—to a human being.

In another aspect the invention relates to a pharmaceutical preparation containing as active substance one or more compounds of general formula (1)—or the pharmaceutically acceptable salts thereof—optionally in combination with conventional excipients and/or carriers.

In another aspect the invention relates to a pharmaceutical preparation comprising a compound of general formula (1)—or one of the pharmaceutically acceptable salts thereof—and at least one other cytostatic or cytotoxic active substance, different from formula (1).

DEFINITIONS

Terms that are not specifically defined here have the meanings that are apparent to the skilled man in the light of the overall disclosure and the context as a whole.

As used herein, the following definitions apply, unless stated otherwise:

The use of the prefix C_(x-y), wherein x and y each represent a natural number (x<y), indicates that the chains or ring structure or combination of chains and ring structure as a whole, specified and mentioned in direct association, may consist of a maximum of y and a minimum of x carbon atoms.

The indication of the number of members in groups that contain one or more heteroatom(s) (heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl) relates to the total atomic number of all the ring members or chain members or the total of all the ring and chain members.

Alkyl denotes monovalent, saturated hydrocarbon chains, which may be present in both straight-chain (unbranched) and branched form. If an alkyl is substituted, the substitution may take place independently of one another, by mono- or polysubstitution in each case, on all the hydrogen-carrying carbon atoms.

The term “C₁₋₅-alkyl” includes for example H₃C—, H₃C—CH₂—, H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—, H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—, H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—, H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— and H₃C—CH₂—CH(CH₂CH₃)—.

Further examples of alkyl are methyl (Me; —CH₃), ethyl (Et; —CH₂CH₃), 1-propyl (n-propyl; n-Pr; —CH₂CH₂CH₃), 2-propyl (i-Pr; iso-propyl; —CH(CH₃)₂), 1-butyl (n-butyl; n-Bu; —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (iso-butyl; i-Bu; —CH₂CH(CH₃)₂), 2-butyl (sec-butyl; sec-Bu; —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (tert-butyl; t-Bu; —C(CH₃)₃), 1-pentyl (n-pentyl; —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂), 3-methyl-1-butyl (iso-pentyl; —CH₂CH₂CH(CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 2,2-dimethyl-1-propyl (neo-pentyl; —CH₂C(CH₃)₃), 2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (n-hexyl; —CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃), 2,3-dimethyl-1-butyl (—CH₂CH(CH₃)CH(CH₃)CH₃), 2,2-dimethyl-1-butyl (—CH₂C(CH₃)₂CH₂CH₃), 3,3-dimethyl-1-butyl (—CH₂CH₂C(CH₃)₃), 2-methyl-1-pentyl (—CH₂CH(CH₃)CH₂CH₂CH₃), 3-methyl-1-pentyl (—CH₂CH₂CH(CH₃)CH₂CH₃), 1-heptyl (n-heptyl), 2-methyl-1-hexyl, 3-methyl-1-hexyl, 2,2-dimethyl-1-pentyl, 2,3-dimethyl-1-pentyl, 2,4-dimethyl-1-pentyl, 3,3-dimethyl-1-pentyl, 2,2,3-trimethyl-1-butyl, 3-ethyl-1-pentyl, 1-octyl (n-octyl), 1-nonyl (n-nonyl); 1-decyl (n-decyl) etc.

By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl etc. without any further definition are meant saturated hydrocarbon groups with the corresponding number of carbon atoms, wherein all isomeric forms are included.

The above definition for alkyl also applies if alkyl is a part of another group such as for example C_(x-y)-alkylamino or C_(x-y)-alkyloxy.

The term alkylene can also be derived from alkyl. Alkylene is bivalent, unlike alkyl, and requires two binding partners. Formally, the second valency is produced by removing a hydrogen atom in an alkyl. Corresponding groups are for example —CH₃ and —CH₂, —CH₂CH₃ and —CH₂CH₂ or >CHCH₃ etc.

The term “C₁₋₄-alkylene” includes for example —(CH₂)—, —(CH₂—CH₂)—, —(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—, —(CH(CH₃)—CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—CH₂—CH₂—CH₂)—, —(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—CH₂—CH₂)—, —(CH₂—CH(CH₃)—CH₂)—, —(CH₂—C(CH₃)₂)—, —(C(CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—, —(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—CH₂)—, —(CH(CH₂CH₂CH₃))—, —(CHCH(CH₃)₂)— and —C(CH₃)(CH₂CH₃)—.

Other examples of alkylene are methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, hexylene etc.

By the generic terms propylene, butylene, pentylene, hexylene etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propylene includes 1-methylethylene and butylene includes 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene.

The above definition for alkylene also applies if alkylene is part of another group such as for example in HO—C_(x-y)-alkylenamino or H₂N—C_(x-y)-alkylenoxy.

Unlike alkyl, alkenyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C—C double bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenyl is formed.

Examples of alkenyl are vinyl (ethenyl), prop-1-enyl, allyl (prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methyl-prop-2-enyl, 2-methyl-prop-1-enyl, 1-methyl-prop-2-enyl, 1-methyl-prop-1-enyl, 1-methylidenepropyl, pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl, 3-methyl-but-1-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl, 2,3-dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl, 2-methylidene-3-methylbutyl, 2,3-dimethyl-but-1-enyl, hexa-1,3-dienyl, hexa-1,4-dienyl, penta-1,4-dienyl, penta-1,3-dienyl, buta-1,3-dienyl, 2,3-dimethylbuta-1,3-diene etc.

By the generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexa-dienyl, heptadienyl, octadienyl, nonadienyl, decadienyl etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propenyl includes prop-1-enyl and prop-2-enyl, butenyl includes but-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1-enyl, 1-methyl-prop-2-enyl etc.

Alkenyl may optionally be present in the cis or trans or E or Z orientation with regard to the double bond(s).

The above definition for alkenyl also applies when alkenyl is part of another group such as for example in C_(x-y)-alkenylamino or C_(x-y)-alkenyloxy.

Unlike alkylene, alkenylene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C—C double bond. If in an alkylene as hereinbefore defined having at least two carbon atoms, two hydrogen atoms at adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenylene is formed.

Examples of alkenylene are ethenylene, propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene, hexenylene etc.

By the generic terms propenylene, butenylene, pentenylene, hexenylene etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propenylene includes 1-methylethenylene and butenylene includes 1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylethenylene and 1,2-dimethylethenylene.

Alkenylene may optionally be present in the cis or trans or E or Z orientation with regard to the double bond(s).

The above definition for alkenylene also applies when alkenylene is a part of another group as in for example HO—C_(x-y)-alkenylenamino or H₂N—C_(x-y)-alkenylenoxy.

Unlike alkyl, alkynyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C—C triple bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynyl is formed.

Examples of alkynyl are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 3-methyl-but-1-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl etc.

By the generic terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propynyl includes prop-1-ynyl and prop-2-ynyl, butynyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-1-ynyl, 1-methyl-prop-2-ynyl, etc.

If a hydrocarbon chain carries both at least one double bond and also at least one triple bond, by definition it belongs to the alkynyl subgroup.

The above definition for alkynyl also applies if alkynyl is part of another group, as in C_(x-y)-alkynylamino or C_(x-y)-alkynyloxy, for example.

Unlike alkylene, alkenylene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C—C triple bond. If in an alkylene as hereinbefore defined having at least two carbon atoms, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynylene is formed.

Examples of alkynylene are ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene, 1,3-dimethylpropynylene, hexynylene etc.

By the generic terms propynylene, butynylene, pentynylene, hexynylene etc. without any further definition are meant all the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propynylene includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and 1,2-dimethylethynylene.

The above definition for alkynylene also applies if alkynylene is part of another group, as in HO—C_(x-y)-alkynyleneamino or H₂N—C_(x-y)-alkynyleneoxy, for example.

By heteroatoms are meant oxygen, nitrogen and sulphur atoms.

Haloalkyl (haloalkenyl, haloalkynyl) is derived from the previously defined alkyl (alkenyl, alkynyl) by replacing one or more hydrogen atoms of the hydrocarbon chain independently of one another by halogen atoms, which may be identical or different. If a haloalkyl (haloalkenyl, haloalkynyl) is to be further substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms.

Examples of haloalkyl (haloalkenyl, haloalkynyl) are —CF₃, —CHF₂, —CH₂F, —CF₂CF₃, —CHFCF₃, —CH₂CF₃, —CF₂CH₃, —CHFCH₃, —CF₂CF₂CF₃, —CF₂CH₂CH₃, —CF═CF₂, —CCl═CH₂, —CBr═CH₂, —Cl═CH₂, —C≡C—CF₃, —CHFCH₂CH₃, —CHFCH₂CF₃ etc.

From the previously defined haloalkyl (haloalkenyl, haloalkynyl) are also derived the terms haloalkylene (haloalkenylene, haloalkynylene). Haloalkylene (haloalkenyl, haloalkynyl), unlike haloalkyl, is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from a haloalkyl.

Corresponding groups are for example —CH₂F and —CHF—, —CHFCH₂F and —CHFCHF— or >CFCH₂F etc.

The above definitions also apply if the corresponding halogen groups are part of another group.

Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.

Cycloalkyl is made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. The systems are saturated. In bicyclic hydrocarbon rings two rings are joined together so that they have at least two carbon atoms together. In spiro-hydrocarbon rings a carbon atom (spiroatom) belongs to two rings together. If a cycloalkyl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Cycloalkyl itself may be linked as a substituent to the molecule via every suitable position of the ring system.

Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl (octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthalene), bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norcaranyl), bicyclo-[3.1.1]heptyl (pinanyl), spiro[2.5]octyl, spiro[3.3]heptyl etc.

The above definition for cycloalkyl also applies if cycloalkyl is part of another group as in C_(x-y)-cycloalkylamino or C_(x-y)-cycloalkyloxy, for example.

If the free valency of a cycloalkyl is saturated, then an alicyclic group is obtained.

The term cycloalkylene can thus be derived from the previously defined cycloalkyl. Cycloalkylene, unlike cycloalkyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkyl. Corresponding groups are for example cyclohexyl and

(cyclohexylene).

The above definition for cycloalkylene also applies if cycloalkylene is part of another group as in HO—C_(x-y)-cycloalkyleneamino or H₂N—C_(x-y)-cycloalkyleneoxy, for example.

Cycloalkenyl is also made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. However, the systems are unsaturated, i.e. there is at least one C—C double bond but no aromatic system. If in a cycloalkyl as hereinbefore defined two hydrogen atoms at adjacent cyclic carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding cycloalkenyl is obtained. If a cycloalkenyl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Cycloalkenyl itself may be linked as a substituent to the molecule via every suitable position of the ring system.

Examples of cycloalkenyl are cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl, cyclobuta-1,3-dienyl, cyclopenta-1,4-dienyl, cyclopenta-1,3-dienyl, cyclopenta-2,4-dienyl, cyclohexa-1,3-dienyl, cyclohexa-1,5-dienyl, cyclohexa-2,4-dienyl, cyclohexa-1,4-dienyl, cyclohexa-2,5-dienyl, bicyclo[2.2.1]hepta-2,5-dienyl (norborna-2,5-dienyl), bicyclo[2.2.1]hept-2-enyl (norbornenyl), spiro[4.5]dec-2-ene etc.

The above definition for cycloalkenyl also applies when cycloalkenyl is part of another group as in C_(x-y)-cycloalkenylamino or C_(x-y)-cycloalkenyloxy, for example.

If the free valency of a cycloalkenyl is saturated, then an unsaturated alicyclic group is obtained.

The term cycloalkenylene can thus be derived from the previously defined cycloalkenyl. Cycloalkenylene, unlike cycloalkenyl, is bivalent and requires two binding partners. Formally the second valency is obtained by removing a hydrogen atom from a cycloalkenyl. Corresponding groups are for example cyclopentenyl and

(cyclopentenylene) etc.

The above definition for cycloalkenylene also applies when cycloalkenylene is part of another group as in HO—C_(x-y)-cycloalkenyleneamino or H₂N—C_(x-y)-cycloalkenyleneoxy, for example.

Aryl denotes a mono-, bi- or tricyclic group with at least one aromatic carbocycle. Preferably it denotes a monocyclic group with six carbon atoms (phenyl) or a bicyclic group with nine or ten carbon atoms (two six-membered rings or one six-membered ring with a five-membered ring), wherein the second ring may also be aromatic or, however, may also be saturated or partially saturated. If an aryl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Aryl itself may be linked as a substituent to the molecule via every suitable position of the ring system. Examples of aryl are phenyl, naphthyl, indanyl (2,3-dihydroindenyl), indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl, tetralinyl), dihydronaphthyl (1,2-dihydronaphthyl), fluorenyl etc.

The above definition of aryl also applies when aryl is part of another group as in arylamino or aryloxy, for example.

If the free valency of an aryl is saturated, then an aromatic group is obtained.

The term arylene can also be derived from the previously defined aryl. Arylene, unlike aryl, is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from an aryl. Corresponding groups are e.g. phenyl and

(o, m, p-phenylene), naphthyl and

etc.

The above definition for arylene also applies when arylene is part of another group as in HO-aryleneamino or H₂N-aryleneoxy for example.

Heterocyclyl denotes ring systems, which are derived from the previously defined cycloalkyl, cycloalkenyl and aryl by replacing one or more of the groups —CH₂-independently of one another in the hydrocarbon rings by the groups —O—, —S— or —NH— or by replacing one or more of the groups ═CH— by the group ═N—, wherein a total of not more than five heteroatoms may be present, at least one carbon atom may be present between two oxygen atoms and between two sulphur atoms or between one oxygen and one sulphur atom and the ring as a whole must have chemical stability. Heteroatoms may optionally be present in all the possible oxidation stages (sulphur sulphoxide —SO, sulphone —SO₂—; nitrogen→N-oxide). In a heterocyclyl there is no heteroaromatic ring, i.e. no heteratom is part of an aromatic system.

A direct result of the derivation from cycloalkyl, cycloalkenyl and aryl is that heterocyclyl is made up of the subgroups monocyclic heterorings, bicyclic heterorings, tricyclic heterorings and spiro-heterorings, which may be present in saturated or unsaturated form. By unsaturated is meant that there is at least one double bond in the ring system in question, but no heteroaromatic system is formed. In bicyclic heterorings two rings are linked together so that they have at least two (hetero)atoms in common. In spiro-heterorings a carbon atom (spiroatom) belongs to two rings together. If a heterocyclyl is substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon and/or nitrogen atoms. Heterocyclyl itself may be linked as a substituent to the molecule via every suitable position of the ring system.

Examples of heterocyclyl are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl, 1,4-dioxanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, 1,3-dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, [1,4]-oxazepanyl, tetrahydrothienyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydro-pyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-S-oxide, 2,3-dihydroazet, 2H-pyrrolyl, 4H-pyranyl, 1,4-dihydropyridinyl, 8-azabicyclo[3.2.1]octyl, 8-azabicyclo[5.1.0]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 2,5-diaza-bicyclo-[2.2.1]heptyl, 1-aza-bicyclo[2.2.2]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 3,9-diaza-bicyclo[4.2.1]nonyl, 2,6-diaza-bicyclo[3.2.2]nonyl, 1,4-dioxa-spiro[4.5]decyl, 1-oxa-3,8-diaza-spiro[4.5]decyl, 2,6-diaza-spiro[3.3]heptyl, 2,7-diaza-spiro[4.4]nonyl, 2,6-diaza-spiro[3.4]octyl, 3,9-diaza-spiro[5.5]undecyl, 2,8-diaza-spiro[4.5]decyl etc.

Further examples are the structures illustrated below, which may be attached via each hydrogen-carrying atom (exchanged for hydrogen):

The above definition of heterocyclyl also applies if heterocyclyl is part of another group as in heterocyclylamino or heterocyclyloxy for example.

If the free valency of a heterocyclyl is saturated, then a heterocyclic group is obtained.

The term heterocyclylene is also derived from the previously defined heterocyclyl. Heterocyclylene, unlike heterocyclyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heterocyclyl. Corresponding groups are for example piperidinyl and

2,3-dihydro-1H-pyrrolyl and

etc.

The above definition of heterocyclylene also applies if heterocyclylene is part of another group as in HO-heterocyclyleneamino or H₂N-heterocyclyleneoxy for example.

Heteroaryl denotes monocyclic heteroaromatic rings or polycyclic rings with at least one heteroaromatic ring, which compared with the corresponding aryl or cycloalkyl (cycloalkenyl) contain, instead of one or more carbon atoms, one or more identical or different heteroatoms, selected independently of one another from among nitrogen, sulphur and oxygen, wherein the resulting group must be chemically stable. The prerequisite for the presence of heteroaryl is a heteroatom and a heteroaromatic system. If a heteroaryl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon and/or nitrogen atoms. Heteroaryl itself may be linked as a substituent to the molecule via every suitable position of the ring system, both carbon and nitrogen. Examples of heteroaryl are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyridyl-N-oxide, pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl-N-oxide, indolyl, isoindolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl, indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl, benzoxazolyl, pyridopyridyl, purinyl, pteridinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, quinolinyl-N-oxide, indolyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide, phthalazinyl-N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide etc.

Further examples are the structures illustrated below, which may be attached via each hydrogen-carrying atom (exchanged for hydrogen):

The above definition of heteroaryl also applies when heteroaryl is part of another group as in heteroarylamino or heteroaryloxy, for example.

If the free valency of a heteroaryl is saturated, a heteroaromatic group is obtained.

The term heteroarylene can therefore be derived from the previously defined heteroaryl. Heteroarylene, unlike heteroaryl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heteroaryl. Corresponding groups are for example pyrrolyl and

etc.

The above definition of heteroarylene also applies when heteroarylene is part of another group as in HO-heteroaryleneamino or H₂N-heteroaryleneoxy, for example.

By substituted is meant that a hydrogen atom which is bound directly to the atom under consideration, is replaced by another atom or another group of atoms (substituent). Depending on the starting conditions (number of hydrogen atoms) mono- or polysubstitution may take place on one atom. Substitution with a particular substituent is only possible if the permitted valencies of the substituent and of the atom that is to be substituted correspond to one another and the substitution leads to a stable compound (i.e. to a compound which is not converted spontaneously, e.g. by rearrangement, cyclisation or elimination).

Bivalent substituents such as ═S, ═NR, ═NOR, ═NNRR, ═NN(R)C(O)NRR, ═N₂ or the like, may only be substituents at carbon atoms, wherein the bivalent substituent ═O may also be a substituent at sulphur. Generally, substitution may be carried out by a bivalent substituent only at ring systems and requires replacement by two geminal hydrogen atoms, i.e. hydrogen atoms that are bound to the same carbon atom that is saturated prior to the substitution. Substitution by a bivalent substituent is therefore only possible at the group —CH₂— or sulphur atoms of a ring system.

Stereochemistry/Solvates/Hydrates: Unless stated otherwise a structural formula given in the description or in the claims or a chemical name refers to the corresponding compound itself, but also encompasses the tautomers, stereoisomers, optical and geometric isomers (e.g. enantiomers, diastereomers, E/Z isomers, etc.), racemates, mixtures of separate enantiomers in any desired combinations, mixtures of diastereomers, mixtures of the forms mentioned hereinbefore (if such forms exist) as well as salts, particularly pharmaceutically acceptable salts thereof. The compounds and salts according to the invention may be present in solvated form (e.g. with pharmaceutically acceptable solvents such as e.g. water, ethanol etc.) or in unsolvated form. Generally, for the purposes of the present invention the solvated forms, e.g. hydrates, are to be regarded as of equal value to the unsolvated forms.

Salts: The term “pharmaceutically acceptable” is used herein to denote compounds, materials, compositions and/or formulations which are suitable, according to generally recognised medical opinion, for use in conjunction with human and/or animal tissue and do not have or give rise to any excessive toxicity, irritation or immune response or lead to other problems or complications, i.e. correspond overall to an acceptable risk/benefit ratio. The term “pharmaceutically acceptable salts” relates to derivatives of the chemical compounds disclosed in which the parent compound is modified by the addition of acid or base. Examples of pharmaceutically acceptable salts include (without being restricted thereto) salts of mineral or organic acids in relation to basic functional groups such as for example amines, alkali metal or organic salts of acid functional groups such as for example carboxylic acids, etc. These salts include in particular acetate, ascorbate, benzenesulphonate, benzoate, besylate, bicarbonate, bitartrate, bromide/hydrobromide, Ca-edetate/edetate, camsylate, carbonate, chloride/hydrochloride, citrate, edisylate, ethane disulphonate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollylarsnilate, hexylresorcinate, hydrabamine, hydroxymaleate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, malate, maleate, mandelate, methanesulphonate, mesylate, methylbromide, methylnitrate, methylsulphate, mucate, napsylate, nitrate, oxalate, pamoate, pantothenate, phenyl acetate, phosphate/diphosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulphamide, sulphate, tannate, tartrate, teoclate, toluenesulphonate, triethiodide, ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumin and procaine. Other pharmaceutically acceptable salts may be formed with cations of metals such as aluminium, calcium, lithium, magnesium, potassium, sodium, zinc, etc. (cf. also Pharmaceutical salts, Birge, S. M. et al., J. Pharm. Sci., (1977), 66, 1-19).

The pharmaceutically acceptable salts of the present invention may be prepared starting from the parent compound which carries a basic or acidic functionality, by conventional chemical methods. Generally, such salts may be synthesised by reacting the free acid or base form of these compounds with a sufficient amount of the corresponding base or acid in water or an organic solvent such as for example ether, ethyl acetate, ethanol, isopropanol, acetonitrile (or mixtures thereof).

Salts of acids other than those mentioned above, which are useful for example for purifying or isolating the compounds from the reaction mixtures (e.g. trifluoroacetates), are also to be regarded as part of the invention.

In a representation such as for example

the letter A has the function of a ring designation in order to make it easier, for example, to indicate the attachment of the ring in question to other rings.

For bivalent groups in which it is crucial to determine which adjacent groups they bind and with which valency, the corresponding binding partners are indicated in brackets, where necessary for clarification purposes, as in the following representations:

or (R²)—C(O)NH— or (R²)—NHC(O)—;

Groups or substituents are frequently selected from among a number of alternative groups/substituents with a corresponding group designation (e.g. R^(a), R^(b) etc). If such a group is used repeatedly to define a compound according to the invention in different molecular parts, it must always be borne in mind that the various uses are to be regarded as totally independent of one another.

By a therapeutically effective amount for the purposes of this invention is meant a quantity of substance that is capable of obviating symptoms of illness or of preventing or alleviating these symptoms, or which prolong the survival of a treated patient.

LIST OF ABBREVIATIONS

aa amino acid Ac acetyl ATP adenosine triphosphate Boc tert.-butyloxycarbonyl BSA bovine serum albumin Bu butyl d day(s) TLC thin layer chromatography DCC dicyclohexylcarbodiimide DCM dichloromethane DEA diethylamine DIC diisopropylcarbodiimide DIPEA N-ethyl-N,N-diisopropylamine (HÜNIG base) DMF N,N-dimethylformamide DMSO dimethylsulphoxide EDC N-(3-dimethylaminopropyl)-N4- ethylcarbodiimide hydrochloride ESI electron spray ionization Et ethyl EtOH ethanol h hour HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyl-uronium hexafluorophosphate HPLC high performance liquid chromatography Hünig base N-ethyl-N,N-diisopropylamine i iso cat. catalyst, catalytic conc. concentrated LC liquid chromatography sln. solution Me methyl MeOH methanol min minutes MPLC medium pressure liquid chromatography MS mass spectrometry MW microwave NMP N-methylpyrrolidone PBS phosphate-buffered saline solution Pd-DPPF 1,1{acute over ( )}-bis(diphenylphosphino)ferrocene- palladium(II)-dichloride dichloromethane PDK1 phosphoinositide-dependent kinase 1 Ph phenyl PI3K phosphatidylinositol-3-kinase PKT protein kinase B Pr propyl R_(f) (Rf) retention factor RP reversed phase RT ambient temperature s second TBTU O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyl-uronium tetrafluoroborate TEA triethylamine tert. tertiary Tf triflate TFA trifluoroacetic acid THF tetrahydrofuran TMS trimethylsilyl Tos tosyl t_(Ret.) retention time (HPLC) TRIS tris(hydroxymethyl)-aminomethane UV ultraviolet

Features and advantage of the present invention will become apparent from the following detailed Examples, which illustrate the fundamentals of the invention by way of example, without restricting its scope:

Preparation of the Compounds According to the Invention General

Unless stated otherwise, all the reactions are carried out in commercially obtainable apparatus using methods that are commonly used in chemical laboratories. Starting materials that are sensitive to air and/or moisture are stored under protective gas and corresponding reactions and manipulations therewith are carried out under protective gas (nitrogen or argon).

The compounds are named according to the Beilstein rules using the Autonom software (Beilstein). If a compound is to be represented both by a structural formula and by its nomenclature, in the event of a conflict the structural formula is decisive.

Microwave reactions are carried out in an initiator/reactor made by Biotage or in an Explorer made by CEM in sealed containers (preferably 2, 5 or 20 mL), preferably with stirring.

Chromatography

Thin layer chromatography is carried out on ready-made TLC plates of silica gel 60 on glass (with fluorescence indicator F-254) made by Merck.

The preparative high pressure chromatography (HPLC) of the example compounds according to the invention is carried out with columns made by Waters (names: Sunfire C18, 5 μm, 30×100 mm Part. No. 186002572; X-Bridge C18, 5 μm, 30×100 mm Part. No. 186002982).

The compounds are eluted using either different gradients of H₂O/acetonitrile or H₂O/MeOH, wherein either 0.1% HCOOH is added to the water (acid conditions). For chromatography under basic conditions H₂O/acetonitrile gradients are also used, and the water is made basic according to the following recipe: 5 mL of an ammonium hydrogen carbonate solution (158 g to 1 L H₂O) and 2 mL ammonia (7M in MeOH) are made up to 1 L with H₂O.

The normal-phase preparative high pressure chromatography (HPLC) of the example compounds according to the invention is carried out with columns made by Macherey & Nagel (name: Nucleosil, 50-7, 40×250 mm) and VDSoptilab (name: Kromasil 100 NH₂, 10 μM, 50×250 mm). The compounds are eluted using different gradients of DCM/MeOH, with 0.1% NH₃ added to the MeOH.

The analytical HPLC (reaction monitoring) of intermediate compounds is carried out with columns made by Agilent, Waters and Phenomenex. The analytical equipment is also provided with a mass detector in each case.

HPLC Mass Spectroscopy/UV Spectrometry

The retention times/MS-ESI⁺ for characterising the example compounds according to the invention are produced using an HPLC-MS apparatus (high performance liquid chromatography with mass detector) made by Agilent. Compounds that elute at the injection peak are given the retention time t_(Ret.)=0.00.

HPLC-Methods Preparative

Prep. HPLC1

HPLC: 333 and 334 Pumps Column: Waters X-Bridge C18, 5 μm, 30 × 100 mm, Part. No. 186002982 Eluant: A: 10 mM NH₄HCO₃ in H₂O; B: acetonitrile (HPLC grade) Detection: UV/Vis-155 Flow: 50 mL/min Gradient: 0.00 min:  5% B 3.00-15.00 min: variable (see individual methods) 15.00-17.00 min: 100% B Prep. HPLC2

HPLC: 333 and 334 Pumps Column: Waters Sunfire C18, 5 μm, 30 × 100 mm, Part. No. 186002572 Eluant: A: H₂O + 0.2% HCOOH; B: acetonitrile (HPLC grade) + 0.2% HCOOH Detection: UV/Vis-155 Flow: 50 mL/min Gradient: 0.00 min:  5% B 3.00-15.00 min: variable (see individual methods) 15.00-17.00 min: 100% B

Analytical LCMSBAS1

HPLC: Agilent 1100 Series MS: Agilent LC/MSD SL Column: Phenomenex Mercury Gemini C18, 3 μm, 2 × 20 mm, Part. No. 00M-4439-B0-CE Eluant: A: 5 mM NH₄HCO₃/20 mM NH₃ in H₂O; B: acetonitrile (HPLC grade) Detection: MS: Positive and negative mode Mass range: 120-900 m/z Flow: 1.00 mL/min Column temp.: 40° C. Gradient: 0.00 min: 5% B 0.00-2.50 min: 5% → 95% B 2.50-2.80 min: 95% B 2.81-3.10 min: 95% → 5% B

FECB3

HPLC: Agilent 1100 Series MS: Agilent LC/MSD SL Column: Waters X-Bridge C18, 2.1 × 50 mm, 3.5 μm Eluant: A: 5 mM NH₄HCO₃/20 mM NH₃ in H₂O; B: acetonitrile (HPLC grade) Detection: MS: Positive and negative mode Mass range: 105-1200 m/z Flow: 1.20 mL/min Column temp.: 35° C. Gradient: 0.01 min: 5% B 0.01-1.25 min: 5% → 95% B 1.25-2.00 min: 95% B 2.00-2.01 min: 95% → 5% B

FECB4/FECBM2

HPLC: Agilent 1100 Series MS: Agilent LC/MSD SL Column: Agilent Zorbax Extend C18, 3.5 μm, 2.1 × 50 mm, Part. No. 735700-902 Eluant: A: 5 mM NH₄HCO₃/20 mM NH₃ in H₂O; B: acetonitrile (HPLC grade) Detection: MS: Positive and negative mode Mass range: 105-1200 m/z Flow: 1.20 mL/min Column temp.: 35° C. Gradient: 0.01 min: 5% B 0.01-1.25 min: 5% → 95% B 1.25-2.00 min: 95% B 2.00-2.01 min: 95% → 5% B

FECS

HPLC: Agilent 1100 Series MS: Agilent LC/MSD SL Column: Agilent Zorbax SB C8, 3.5 μm, 2.1 × 50 mm, Part. No. 871700-906 Eluant: A: H₂O + 0.2% HCOOH; B: acetonitrile (HPLC grade) + 0.2% HCOOH Detection: MS: Positive and negative mode Mass range: 105-1200 m/z Flow: 1.20 mL/min Column temp.: 35° C. Gradient: 0.01 min: 5% B 0.01-1.25 min: 5% → 95% B 1.25-2.00 min: 95% B 2.00-2.01 min: 95% → 5% B

1_BAS

HPLC: Agilent 1100 Series MS: 1100 Series LC/MSD SL (MM-ES + APCI, +3000 V, Quadrupole, G1956B) Column: Waters X-Bridge C18, 3.5 μm, 135 Å, 2.1 × 30 mm, Part. No.: 186003020 Eluant: A: 5 mM NH₄HCO₃/20 mM NH₃ (pH = 9.5); B: acetonitrile (HPLC grade) Detection: MS: Positive mode Mass range: 120-750 m/z Flow: 1.00 mL/min Column temp.: 35° C. Gradient: 0.0-1.0 min 15% → 95% B 1.0-1.6 min 95% B 1.6-1.7 min 95% → 15% B 1.7-2.3 min 15% B

1_FEC

HPLC: Agilent 1100 Series MS: 1200 Series LC/MSD (API-ES + 3000 V, Quadrupole, G6140A) Column: Agilent Zorbax SB C8, 3.5 μm, 80 Å, 2.1 × 50 mm, Part. No.: 871700-906 Eluant: A: water + 0.1% HCOOH; B: acetonitrile (HPLC grade) + 0.1% HCOOH Detection: MS: Positive mode Mass range: 120-750 m/z Flow: 1.10 mL/min Column temp.: 45° C. Gradient: 0.0-1.75 min 15% → 95% B 1.75-1.9 min 95% B 1.9-1.92 min 95% → 15% B 1.92-2.1 min 15% B

1_BAS_MeOH_POS

HPLC: Agilent 1100 Series MS: 1100 Series LC/MSD SL (MM-ES + APCI, +3000 V, Quadrupole, G1956B) Column: Waters X-Bridge C18, 3.5 μm, 135 Å, 2.1 × 30 mm, Part. No.: 186003020 Eluant: A: 5 mM NH₄HCO₃/20 mM NH₃ (pH = 9.5); B: MeOH (HPLC grade) Detection: MS: Positive Mass range: 120-750 m/z Flow: 1.00 mL/min Column temp.: 40° C. Gradient: 0.0-1.0 min 20% → 95% B 1.0-2.0 min 95% B 2.0-2.1 min 95% → 20% B 2.1-2.3 min 20% B

BFEC

HPLC: Agilent 1100/1200 Series MS: Agilent 1100 LC/MSD SL Column: Waters X-Bridge C18, 5 μm, 2.1 × 50 mm Eluant: A: H₂O + 0.1% NH₄OH/NH₄HCO₃; B: acetonitrile Detection: MS: Positive and negative mode Mass range: 100-1200 m/z Flow: 1.00 mL/min Column temp.: 35° C. Gradient: 0.01 min: 5% B 0.01-1.50 min: 5% → 100% B 1.50-2.10 min: 100% B 2.10-2.20 min: 100% → 5% B

AFEC

HPLC: Agilent 1100/1200 Series MS: Agilent 1100 LC/MSD SL Column: Waters Sunfire C18, 5 μm, 2.1 × 50 mm Eluant: A: H₂O + 0.1% HCOOH; B: acetonitrile Detection: MS: Positive and negative mode Mass range: 100-1200 m/z Flow: 1.00 mL/min Column temp.: 35° C. Gradient: 0.01 min: 5% B 0.01-1.50 min: 5% → 100% B 1.50-2.10 min: 100% B 2.10-2.20 min: 100% → 5% B

FECS2

HPLC: Agilent 1100/1200 Series MS: Agilent 1100 LC/MSD SL Column: Sunfire C18, 5 μm, 2.1 × 50 mm Eluant: A: H₂O + 0.2% HCOOH; B: MeOH Detection: ESI Mass range: 100-1200 m/z Flow: 1.20 mL/min Column temp.: 35° C. Gradient: 0.01 min: 5% B 0.01-1.50 min: 5% → 100% B 1.50-2.00 min: 100% B

FECBM4

HPLC: Agilent 1100/1200 Series MS: Agilent 1100 LC/MSD SL Column: Waters Sunfire, 5 μm, 2.1 × 50 mm Eluant: A: H₂O + 5 mM NH₄HCO₃, 19 mM NH₃; B: MeOH Detection: MS: Positive and negative mode Mass range: 100-1200 m/z Flow: 1.20 mL/min Column temp.: 35° C. Gradient: 0.01 min: 5% B 0.01-1.25 min: 5% → 95% B 1.25-1.50 min: 95% → 100% B 1.50-2.25 min 100% B

FECB6

HPLC: Agilent 1100/1200 Series MS: Agilent 1100 LC/MSD SL Column: Waters X-Bridge C18, 5 μm, 2.1 × 50 mm Eluant: A: H₂O + 5 mM NH₄HCO₃, 19 mM NH₃; B: MeOH Detection: ESI Mass range: 100-1200 m/z Flow: 1.20 mL/min Column temp.: 35° C. Gradient: 0.01 min: 5% B 0.01-1.24 min: 5% → 100% B 1.24-2.10 min: 100% B

FSUN

HPLC: Agilent 1100/1200 Series MS: Agilent 1100 LC/MSD SL Column: Waters Sunfire, 3.5 μm, 2.1 × 50 mm Eluant: A: H₂O + 0.2% HCOOH; B: CH₃CN Detection: ESI Mass range: 100-1200 m/z Flow: 1.20 mL/min Column temp.: 35° C. Gradient: 0.01 min: 5% B 0.01-1.50 min: 5% → 95% B 1.50-2.00 min: 100% B

FSUN2

HPLC: Agilent 1100/1200 Series MS: Agilent 1100 LC/MSD SL Column: Waters Sunfire, 5.0 μm, 2.1 × 50 mm Eluant: A: H₂O + 0.2% HCOOH; B: CH₃CN Detection: ESI Mass range: 100-1200 m/z Flow: 1.20 mL/min Column temp.: 35° C. Gradient: 0.01 min: 5% B 0.01-1.50 min: 5% → 95% B 1.50-2.00 min: 100% B

The compounds according to the invention are prepared by the methods of synthesis described hereinafter, in which the substituents of the general formulae have the meanings given hereinbefore. These methods are intended as an illustration of the invention, without restricting its subject matter and the scope of the compounds claimed to these examples. Where the preparation of starting compounds is not described, they are commercially obtainable or may be prepared analogously to known compounds or methods described herein. Substances described in the literature are prepared according to the published methods of synthesis.

a) Synthesis of Free Cyclic Carboxylic Acids A

The method of synthesising the nitrogen-containing heterocyclic carboxylic acids A depends on the number and position of the cyclic nitrogens in the ring Q^(b).

Starting from the esters A.a the grouping Q^(a)-CR¹R²— may be incorporated by nucleophilic substitution at the component A.b, which is activated by an electron-withdrawing leaving group LG, e.g. a halogen, triflate or mesylate. A.a is optionally deprotonated for this purpose by the addition of a base.

A pyridazinone ring system (Q^(b)=pyridazinone) is synthesised starting from pyruvic acid derivatives which are cyclised with cyanoacetohydrazides. Subsequent saponification of the nitrile yields the corresponding carboxylic acid (Helv. Chim. Acta, 1954, 37, 1467), which after esterification yields the desired pyridazinonecarboxylic acid ester A.a. This is reacted in a nucleophilic substitution with A.b and subsequently saponified to form the desired carboxylic acid A.

A pyrimidinone ring system (Q^(b)=pyrimidinone) is synthesised by cyclisation of malonic acid diester derivatives with amidines. The pyrimidinonecarboxylic acid ester A.a obtained is reacted in a nucleophilic substitution with A.b and subsequently saponified to form the desired carboxylic acid A (WO 2010/007114, WO 2010/007116).

A pyridinone ring system (Q^(b)=pyridinone) is synthesised starting from malonic acid-diester derivatives A.d. The derivatives used are di- and trielectrophiles, which cyclise when reacted with amines A.c (WO 2010/007114, WO 2010/007116).

A pyrazinone ring system (Q^(b)=pyrazinone) is synthesised starting from glyoxal derivatives and aminomalonamide amidines. First of all the corresponding amino-pyrazinecarboxamides are obtained, which are saponified to form the carboxylic acid. After hydrolysis of the amine by diazotisation and esterification of the carboxylic acid the desired pyrazinone ring system A.a is obtained (J. Am. Chem. Soc., 1959, 81, 2472-4). This is reacted in a nucleophilic substitution with A.b and then saponified to form the desired carboxylic acid A.

A pyrazolone ring system (Q^(b)=pyrazolone) is obtained starting from malonic acid diester derivatives A.d, which cyclise with hydrazines A.e. The group LG is not a leaving group in the true sense but an electrophilic group, particularly a carbonyl, to which the hydrazine is added.

Using the methods of synthesis described above, starting from the cyclic carboxylic acid esters A.a or their precursors A.d after reaction with A.b or A.c, first of all carboxylic acid esters A* are obtained. These are each saponified to form the free acid A. In the grouping —COOR″, it is possible to have groups R″ which make this saponification easy and gentle. Such groups include in particular methyl, ethyl, tert-butyl and benzyl esters, wherein others are known to the skilled man from their general specialist knowledge.

The required educts A.b, A.c and A.e, as well as A.a and A.d, are commercially obtainable, already described in the literature or may be prepared analogously to published methods.

Method for Synthesising A.1

Malonic acid diester derivative A.d.1 (5.00 g, 25.0 mmol) is taken up in 40 mL 2-butanol, cooled to 5° C. and mixed with amine A.c.1 (3.00 mL, 25.1 mmol), which has been taken up in 10 mL 2-butanol. The reaction mixture is stirred for 1 h at 20° C., diluted with a further 150 mL of 2-butanol and heated to 100° C. for 48 h. Then the reaction mixture is combined with 50 mL 2 N aqueous sodium hydroxide solution and 50 mL 2 N methanolic sodium hydroxide solution and stirred for 2 h at 20° C. The reaction mixture is acidified with HCl (50 mL, 1 N) and extracted with DCM (3×50 mL), dried on MgSO₄, filtered, the solvent is eliminated in vacuo and A.1 (6.08 g, 90%; MS (M+H)⁺=266; t_(Ret.)=0.00 min; method LCMSBAS1) is obtained.

Compounds A.2-A.24-3 are prepared analogously to A.1 (Table 1):

MS (M ± H)^(±); # Structure t_(Ret.) HPLC [min] HPLC method A.1

M + H = 266; t_(Ret.) = 0.00 LCMSBAS1 A.2

M − H = 228; t_(Ret.) = 0.00 LCMSBAS1 A.3

M − H = 246; t_(Ret.) = 0.00 LCMSBAS1 A.4

M − H = 246; t_(Ret.) = 0.00 LCMSBAS1 A.5

M − H = 278; t_(Ret.) = 0.50 LCMSBAS1 A.6

M + H = 280; t_(Ret.) = 0.43 1_BAS_MEOH_POS A.7

M + H = 244; t_(Ret.) = 0.42 1_BAS_MEOH_POS A.8

M + H = 244; t_(Ret.) = 0.40 1_BAS_MEOH_POS A.9

M + H = 260; t_(Ret.) = 0.20 1_BAS_MEOH_POS A.10

M + H = 260; t_(Ret.) = 0.20 1_BAS_MEOH_POS A.11

M + H = 278; t_(Ret.) = 0.00 LCMSBAS1 A.12

M + H = 296; t_(Ret.) = 0.00 LCMSBAS1 A.13

M + H = 296; t_(Ret.) = 0.00 LCMSBAS1 A.14

M + H = 274; t_(Ret.) = 0.27 1_BAS_MEOH_POS A.15

M + H = 280; t_(Ret.) = 0.48 1_BAS_MEOH_POS A.16

M + H = 274; t_(Ret.) = 0.24 1_BAS_MEOH_POS A.17

M + H = 266; t_(Ret.) = 0.00 LCMSBAS1 A.18

M + H = 265; t_(Ret.) = 1.66 FECS A.19

M + H = 220; t_(Ret.) = 0.10 1_BAS_MEOH_POS A.20

M − H = 234; t_(Ret.) = 0.00 LCMSBAS1 A.21

M − H = 218; t_(Ret.) = 0.00 LCMSBAS1 A.22

M − H = 272; t_(Ret.) = 0.71 1_BAS_MEOH_POS A.23

M − H = 278; t_(Ret.) = 0.50 LCMSBAS1 A.24

M + H = 244; t_(Ret.) = 0.42 1_BAS_MEOH_POS A.24-1

M + H = 284; t_(Ret.) = 0.38 LCMSBAS1 A.24-2

n.d. A.24-3

n.d.

Method of Synthesising A.25

Sodium hydride (60%; 1.40 g, 36.0 mmol) is placed in DMF (70 mL), mixed with carboxylic acid ester A.a.1 (5.00 g, 32.0 mmol) and stirred for 45 min at 20° C. Then benzylbromide A.b.1 (4.10 mL, 32.0 mmol) is metered in and the mixture is stirred for a further 3 h at 20° C. The reaction mixture is combined with HCl (50 mL, 1 N) and DCM (50 mL), the organic phase is separated off and extracted again with HCl (2×30 mL). Then the organic phase is dried, the solvent is eliminated in vacuo and carboxylic acid ester A*.25 (10.0 g, 89%; HPLC-MS: MS (M+H)⁺=281; t_(Ret.)=1.57 min; method FEC3) is obtained.

Carboxylic acid ester A*.25 (1.9 g, 5.6 mmol) is taken up in MeOH (7.3 mL) and mixed with NaOH (6.2 mL, 1 M). After 16 h at 20° C. the mixture is diluted with water and extracted with DCM. The organic phase is discarded, the aqueous phase is acidified and extracted with DCM. The organic phase is dried on Na₂SO₄, filtered, the solvent is eliminated in vacuo and the free carboxylic acid A.25 (694 mg, 47%; HPLC-MS: MS (M+H)⁺=267; t_(Ret.)=0.29 min; method FECB4) is obtained.

Method of Synthesising A.26

Sodium hydride (60%; 105 mg, 2.60 mmol) is placed in DMF (1.50 mL), mixed with carboxylic acid ester A.a.2 (400 mg, 2.40 mmol) and stirred for 45 min at 20° C. Then benzyl bromide A.b.1 (0.31 mL, 2.4 mmol) is metered in and the mixture is stirred for a further 48 h at 20° C. The reaction mixture is combined with HCl (50 mL, 1 N) and DCM (50 mL), the organic phase is separated off and extracted again with HCl (2×30 mL). Then the organic phase is dried, the solvent is eliminated in vacuo and carboxylic acid ester A*.26 (487 mg, 69%; HPLC-MS: MS (M+H)⁺=295; t_(Ret.)=2.09 min; method AFEC) is obtained.

Carboxylic acid ester A*.26 (487 mg, 1.71 mmol) is taken up in MeOH (4.0 mL) and mixed with NaOH (2.0 mL, 1 N). After 2 h at 20° C. the mixture is diluted with water and extracted with DCM. The organic phase is discarded, the aqueous phase is acidified and extracted with DCM. The organic phase is dried on Na₂SO₄, the solvent is eliminated in vacuo and the free carboxylic acid A.26 (HPLC-MS: MS (M−H)⁻⁼²⁷⁹; t_(Ret.)=0.00 min; method LCMSBAS1) is obtained.

Compounds A.27-A.33 are prepared analogously to compound A.26 and if necessary subjected to chiral chromatography before the saponification (Table 2):

# Structure MS (M ± H)^(±); t_(Ret.) HPLC [min] HPLC method A.26

M − H = 279; t_(Ret.) = 0.00 LCMSBAS1 A.27

M + H = 265; t_(Ret.) = 0.40 LCMSBAS1 A.28*

M + H = 263; t_(Ret.) = 0.42 LCMSBAS1 A.29*

M + H = 263; t_(Ret.) = 0.42 LCMSBAS1 A.30*

M + H = 277; t_(Ret.) = 0.50 LCMSBAS1 A.31*

M + H = 277; t_(Ret.) = 0.50 LCMSBAS1 A.32*

M + H = 270; t_(Ret.) = 0.48 LCMSBAS1 A.33*

M + H = 270; t_(Ret.) = 0.48 LCMSBAS1 *Gilson HPLC apparatus, chiral column (Daicel Chiralpack IC, 250 × 20 mm). Eluant: 35% n-heptane, 65% DCM/EtOH/diethylamine (2000:100:2.6)

Method of Synthesising A.34

Carboxylic acid ester ED.1 (2.00 g, 10.4 mmol) is placed in dioxane (9.0 mL), combined with HCl (10.4 mL, 1 M) and stirred for 20 h at 90° C. Then the reaction mixture is cooled to 0° C., the precipitate is filtered off, washed with water and pyridazinonic acid Z.1 (955 mg, 53%; HPLC-MS: MS (M−H)⁻=173; t_(Ret.)=0.00 min; method LCMSBAS1) is obtained.

Pyridazinonic acid Z.1 (955 mg, 5.4 mmol) is placed in MeOH (6.0 mL), combined with HCl (6.0 mL, 4M in dioxane) and stirred for 20 h at 50° C. The reaction mixture is combined with H₂O and DCM, the organic phase is separated off and extracted with H₂O (2×10 mL). Then the organic phase is dried on MgSO₄, filtered off, the solvent is eliminated in vacuo and carboxylic acid ester A.a.3 (890 mg, 86%; HPLC-MS: MS (M+H)⁺=189; t_(Ret.)=1.47 min; method AFEC) is obtained.

Sodium hydride (60%; 93 mg, 2.3 mmol) is placed in DMF (1.5 mL), combined with carboxylic acid ester A.a.3 (397 mg, 2.10 mmol) and stirred for 45 min at 20° C. Then benzyl bromide A.b.1 (0.27 mL, 2.1 mmol) is metered in and the mixture is stirred for a further 2 h at 20° C. The reaction mixture is combined with HCl (5 mL, 1 N) and DCM (5 mL), the organic phase is separated off and extracted again with HCl (2×5 mL). Then the organic phase is dried on MgSO₄, filtered off, the solvent is eliminated in vacuo and carboxylic acid ester A*.34 (922 mg, 98%; HPLC-MS: MS (M+H)⁺=315; t_(Ret.)=2.2 min; method AFEC) is obtained.

Carboxylic acid ester A*.34 (470 mg, 1.00 mmol) is taken up in MeOH (3.0 mL) and combined with 1 N NaOH (1.3 mL). After 5 h at 20° C. the mixture is diluted with water and extracted with DCM. The organic phase is discarded, the aqueous phase is acidified with HCl (5 mL, 1 M) and extracted with DCM (3×5 mL). The organic phase is dried, the solvent is eliminated in vacuo and the free carboxylic acid A. 34 (149 mg, 48%; HPLC-MS: MS (M−H)⁻=299; t_(Ret.)=0.76 min; method LCMSBAS1) is obtained.

Method of Synthesising A.35

Carboxylic acid A.34 (4.00 g, 13.0 mmol) is placed in MeOH (40 mL), combined with KtBuO (30%, 3.80 g, 32.0 mmol) and heated to 160° C. for 12 min. The reaction mixture is combined with HCl (20 mL, 1 N) and DCM (30 mL), the organic phase is separated off and extracted with HCl (2×20 mL, 1 N). Then the organic phase is dried on Na₂SO₄, filtered off, the solvent is eliminated in vacuo and carboxylic acid A.34 (3.62 g, 94%; HPLC-MS: MS (M−H)⁻=295; t_(Ret.)=1.00 min; method 1_FEC) is obtained.

Compounds A.36 and A.37 are prepared analogously to compound A.35 (Table 3):

MS (M ± H)^(±); # Structure t_(Ret.) HPLC [min] HPLC method A.34

M − H = 299; t_(Ret.) = 0.76 LCMSBAS1 A.35

M − H = 295; t_(Ret.) = 1.00 1_FEC A.36

M + H = 311; t_(Ret.) = 1.14 LCMSBAS1 A.37

M + H = 335; t_(Ret.) = 1.32 LCMSBAS1

Method of Synthesising A.38

Carboxylic acid ED.2 (300 mg, 2.20 mmol) is placed in conc. H₂SO₄ (1.3 mL), cooled to 0° C., a mixture of NaNO₂ (149 mg, 2.20 mmol) in conc. H₂SO₄ (1.6 mL) is added dropwise and the mixture is stirred for 1 h. Then the reaction mixture is added dropwise to an ice-water mixture with vigorous stirring, the precipitate formed is filtered off and pyrazinonic acid Z.2 (200 mg, 66%; MS (M−H)⁻=139; t_(Ret.)=0.00 min; method LCMSBAS1) is obtained.

Pyrazinonic acid Z.2 (200 mg, 1.4 mmol) is placed in MeOH (10 mL), combined with HCl (0.1 mL, 4 M in dioxane) and stirred for 12 h at 20° C. Then the solvent is removed and carboxylic acid ester A.a.4 (212 mg, 96%; HPLC-MS: MS (M−H)⁻=153; t_(Ret.)=0.00 min; method LCMSBAS1) is obtained.

Sodium hydride (60%; 61 mg, 1.5 mmol) is placed in DMF (1.2 mL), combined with carboxylic acid ester A.a.4 (212 mg, 1.4 mmol) and stirred for 45 min at 20° C. Then benzyl bromide A.b.1 (0.18 mL, 1.4 mmol) is metered in and the mixture is stirred for a further 24 h at 20° C. The reaction mixture is combined with HCl (5 mL, 1 M) and DCM (5 mL), the organic phase is separated off and extracted with HCl (2×5 mL, 1 N). Then the organic phase is dried on Na₂SO₄, filtered off, the solvent is eliminated in vacuo and carboxylic acid ester A*.38 (166 mg, 43%; HPLC-MS: MS (M+H)⁺=281; t_(Ret.)=1.63 min; method FECS) is obtained.

Carboxylic acid ester A*.38 (166 mg, 0.60 mmol) is taken up in MeOH (4.0 mL) and combined with NaOH (0.71 mL, 1 M). After 5 h at 20° C. the mixture is diluted with water and extracted with DCM. The organic phase is discarded, the aqueous phase is acidified with HCl (5 mL, 1 M) and extracted with DCM. The organic phase is dried on Na₂SO₄, filtered off, the solvent is eliminated in vacuo and the free carboxylic acid A. 38 (150 mg, 95%; HPLC-MS: MS (M+H)⁺=267; t_(Ret.)=1.59 min; method FECS) is obtained.

Method of Synthesising A.39 and A.40

Acetyldiethyl malonate A.d.2 (100 mg 0.49 mmol) is placed in conc. acetic acid (0.5 mL) and combined with benzylhydrazine A.e.1 (97 mg, 0.49 mmol). The mixture is stirred for 3 h at 95° C. Then the solvent is removed and carboxylic acid ester A*.39 (45 mg, 35%; HPLC-MS: MS (M+H)⁺=261; t_(Ret.)=0.39 min; method LCMSBAS1) is obtained.

Carboxylic acid ester A*.39 (22 mg, 0.09 mmol) is placed in THF (0.3 mL) and combined with Cs₂CO₃ (30 mg, 0.09 mmol). After 15 min at 20° C. MeI (5 μL, 0.09 mmol) is added and the mixture is stirred for a further 16 h at 20° C. After elimination of the solvent carboxylic acid ester A*.40 (15 mg, 65%; HPLC-MS: MS (M+H)⁺=275; t_(Ret.)=1.24 min; method LCMSBAS1) is obtained.

Carboxylic acid ester A*.40 (35 mg, 0.13 mmol) is placed in THF (0.6 mL), combined with NaOH (0.5 mL, 1 N) and stirred for 4 h at 50° C. The reaction mixture is combined with HCl (3 mL, 1 N) and DCM, the organic phase is separated off, extracted with HCl (2×5 mL, 1 N), dried, the solvent is eliminated in vacuo and carboxylic acid A.40 (31 mg, 99%; HPLC-MS: MS (M+H)⁺=247; t_(Ret.)=1.59 min; method FSUN) is obtained.

Compounds A.41-A.46 are prepared analogously to compound A.40 and if necessary subjected to chiral chromatography before the saponification (Table 4):

MS (M ± H)^(±); # Structure t_(Ret.) HPLC [min] HPLC method A.39

n.v. — A.40

M + H = 247; t_(Ret.) = 1.59 FSUN A.41

M + H = 265; t_(Ret.) = 1.77 FECS2 A.42

M + H = 283; t_(Ret.) = 0.39 LCMSBAS1 A.43

M + H = 301; t_(Ret.) = 0.39 LCMSBAS1 A.44*

M + H = 297; t_(Ret.) = 0.40 LCMSBAS1 A.45*

M + H = 297; t_(Ret.) = 0.40 LCMSBAS1 A.46

M + H = 313; t_(Ret.) = 0.56 1_FEC *Gilson HPLC apparatus, chiral column (Daicel Chiralpack IC, 250 × 20 mm). Eluant: 35% n-heptane, 65% DCM/EtOH/diethylamine (2000:100:2.6)

b) Synthesis of Propargylamides C

The amides C required are synthesised by coupling a propargylamine B with the carboxylic acid A. The amide coupling is assisted by coupling reagents such as for example DCC, DIC, TBTU, HATU, EDC or the like, or the formation of the corresponding acid chloride.

The synthesis components which are to be used in the above reaction schemes are optionally provided with common protective groups when used. Therefore, additional intermediate steps may be needed to eliminate these protective groups.

With regard to the feasibility of the reaction methods illustrated and described in the above reaction schemes reference is made to WO 2008/005457. In the cited specification, pyridinonecarboxylic acids A are amidated in a variety of ways.

Method of Synthesising C.1

Carboxylic acid A.25 (1.00 g, 3.75 mmol) is placed in DCM (10 mL), combined with TBTU (1.73 g, 5.36 mmol), propargylamine B.1 (0.29 mL, 4.10 mmol) and NEt₃ (1.3 mL, 9.5 mmol) and stirred for 12 h at 20° C. The reaction mixture is combined with water and DCM, the organic phase is separated off and extracted 2× with water. Then the organic phase is dried on Na₂SO₄, the solvent is eliminated in vacuo, the crude product is purified by chromatography (90:10 to 60:40 in 12 min H₂O/CH₃CN) and carboxylic acid amide C.1 (940 mg, 83%; HPLC-MS: MS (M+H)⁺=304; t_(Ret.)=1.45 min; method LCMSBAS1) is obtained.

Propargylamides C.2-C.43 are prepared analogously to propargylamide C.1 (Table 5).

MS (M ± H)^(±); # Structure t_(Ret.) HPLC [min] HPLC method C.1

M + H = 304; t_(Ret.) = 1.45 LCMSBAS1 C.2

M + H = 267; t_(Ret.) = 1.43 LCMSBAS1 C.3

M + H = 285; t_(Ret.) = 1.42 LCMSBAS1 C.4

M + H = 285; t_(Ret.) = 1.45 LCMSBAS1 C.5

M + H = 303; t_(Ret.) = 1.53 LCMSBAS1 C.6

M + H = 317; t_(Ret.) = 1.66 LCMSBAS1 C.7

M + H = 317; t_(Ret.) = 1.66 LCMSBAS1 C.8

M + H = 281; t_(Ret.) = 1.53 LCMSBAS1 C.9

M + H = 281; t_(Ret.) = 1.53 LCMSBAS1 C.10

M + H = 297; t_(Ret.) = 1.31 1_FEC C.11

M + H = 297; t_(Ret.) = 1.31 1_FEC C.12

M + H = 315; t_(Ret.) = 1.33 LCMSBAS1 C.13

M + H = 333; t_(Ret.) = 1.42 LCMSBAS1 C.14

M + H = 333; t_(Ret.) = 1.42 LCMSBAS1 C.15

M + H = 303; t_(Ret.) = 1.52 LCMSBAS1 C.16

M − H = 255; t_(Ret.) = 0.86 LCMSBAS1 C.17

M + H = 273; t_(Ret.) = 1.35 LCMSBAS1 C.18

M + H = 257; t_(Ret.) = 0.72 1_FEC C.19

M + H = 304; t_(Ret.) = 1.66 LCMSBAS1 C.20

M + H = 318; t_(Ret.) = 1.73 LCMSBAS1 C.21

M + H = 300; t_(Ret.) = 1.68 LCMSBAS1 C.22

M + H = 300; t_(Ret.) = 1.68 LCMSBAS1 C.23

M + H = 314; t_(Ret.) = 1.75 LCMSBAS1 C.24

M + H = 314; t_(Ret.) = 1.75 LCMSBAS1 C.25

M + H = 307; t_(Ret.) = 1.62 LCMSBAS1 C.26

M + H = 307; t_(Ret.) = 1.62 LCMSBAS1 C.27

M + H = 334; t_(Ret.) = 1.62 LCMSBAS1 C.28

M + H = 348; t_(Ret.) = 1.93 LCMSBAS1 C.29

M + H = 372; t_(Ret.) = 1.80 LCMSBAS1 C.30

M + H = 334; t_(Ret.) = 1.88 LCMSBAS1 C.31

M + H = 390; t_(Ret.) = 1.86 1_FEC C.32

M + H = 338; t_(Ret.) = 1.15 1_FEC C.33

M + H = 284; t_(Ret.) = 1.75 FECB6 C.34

M + H = 302; t_(Ret.) = 1.79 FECB6 C.35

M + H = 320; t_(Ret.) = 1.37 LCMSBAS1 C.36

M + H = 338; t_(Ret.) = 1.41 LCMSBAS1 C.37

M + H = 334; t_(Ret.) = 1.42 LCMSBAS1 C.38

M + H = 334; t_(Ret.) = 1.42 LCMSBAS1 C.39

M + H = 350; t_(Ret.) = 1.53 1_FEC C.40

M + H = 318; t_(Ret.) = 0.98 1_FEC C.41

M + H = 321; t_(Ret.) = 1.23 LCMSBAS1 C.42

n.d. C.43

n.d.

c) Synthesis of Quinazoline, Quinoxaline and Quinoline Compounds D (EWG-Q^(H))

The ring systems Q^(H) of compounds according to the invention, i.e. embodiments Q^(H)-2a to Q^(H)-2f, can be incorporated in the target structures by various methods. Starting from bisfunctional components D*, which are activated by an electron-withdrawing group EWG, particularly chlorine, bromine or iodine, and a further group which enables the substituents R⁵, R⁶, R⁷ and R⁸ to be inserted in their respective positions, first of all the substituent R⁵, R⁶, R⁷ or R⁸ can be introduced and in this way the component D is obtained (Q^(H)*→Q^(H)). D is then reacted in a SONOGASHIRA reaction with C to form the compound according to the invention (1) (cf. also reaction scheme D). In an alternative sequence first D* may be reacted with C in the SONOGASHIRA reaction and only then is the substituent R⁵, R⁶, R⁷ or R⁸ introduced (cf. also reaction scheme F). The position of the group EWG on the ring system Q^(H)/Q^(H)* denotes the linkage point of the ring system to the linker unit, i.e. in this case to the C—C triple bond.

As another alternative it is possible to carry out the SONOGASHIRA reaction between N-protected propargylamines B and D* or D and couple the intermediates R⁴—NH-L-Q^(H) or R⁴—NH-L-Q^(H)* obtained with the acids A (cf. this method of inserting alkenyl linkers, reaction schemes G and H).

The final substituents R⁵, R⁶, R⁷ or R⁸ (Q^(H)→Q^(H)*) are introduced for example by nucleophilic substitution, SUZUKI coupling, amidation (optionally activation with DCC, DIC, TBTU, HATU, EDC or the like), reductive alkylation or, however, during the ring formation of the corresponding system Q^(H). Other possibilities are BUCHWALD-HARTWIG, NEGISHI, HECK or SONOGASHIRA reactions. The activating groups that are suitable for these reactions are well known in the art.

The synthesis of bisfunctional components D* which are suitable for incorporating the ring systems Q^(H) in compounds (1) according to the invention, is described in the literature. They may be prepared using published methods or can be directly obtained commercially:

-   Q^(H)-2b: e.g. Tetrahedron Lett. 2002, 6209; WO 2007/133637; -   Q^(H)-2c: e.g. WO 2007/104560; WO 2008/020302; WO 2006/071017 -   Q^(H)-2d: e.g. WO 2008/138878; -   Q^(H)-2e: e.g. U.S. Pat. No. 4,996,213 (S.3) and J. Org. Chem. 1971,     1331; Polish J. Chem. 1983, 587; -   Q^(H)-2f: e.g. US 2009/036430; WO 2009/003669; WO 2006/135993;

Method of Synthesising the Quinazolines D*.1 and D.1

Anthranilic acid ED.3 (32.5 g, 211 mmol) is placed in glacial acetic acid (400 mL), and ICl (35.0 g, 211 mmol) in glacial acetic acid (100 mL) is added dropwise thereto. The reaction mixture is stirred for 1 h at 20° C., then diluted again with glacial acetic acid (250 mL) and stirred for 1 h at 20° C. The reaction mixture is filtered, the filter cake is washed with glacial acetic acid and acetonitrile and anthranilic acid Z.3 (45.3 g, 70%; HPLC-MS: MS (M−H)⁻=276; t_(Ret.)=0.00 min; method LCMSBAS1) is obtained.

Anthranilic acid Z.3 (17.3 g, 50.0 mmol) and formamidine acetate (25.0 g, 238 mmol) are placed in EtOH (500 mL) and heated to 95° C. for 6 h. Then the reaction mixture is cooled to 50° C., the precipitate is filtered off, the filter cake is washed with EtOH and quinazolone Z.4 (11.8 g, 69%; HPLC-MS: MS (M−H)⁻=285; t_(Ret.)=1.13 min; method LCMSBAS1) is obtained.

Quinazolone Z.4 (451 mg, 1.51 mmol) is combined with DIPEA (0.5 mL) and POCl₃ (2.5 mL, 26.7 mmol) and heated to 125° C. for 1.5 h in the MW reactor. Then the reaction mixture is evaporated to dryness and quinazoline D*.1 (456 mg, 100%) is obtained.

Quinazoline D*.1 (530 mg, 1.70 mmol) is combined with methylamine (15 mL, 2M in THF) in the ultrasound bath and stirred for 1 h at 20° C. The solvent is removed, the crude product is purified by chromatography (EtOAc) and quinazoline D.1 (320 mg, 62%; HPLC-MS: MS (M+H)⁺=300; t_(Ret.)=1.43 min; method LCMSBAS1) is obtained.

Method of Synthesising the Azaquinazolines D*.2 and D.2

Pyridine ED.4 (10.0 g, 54.5 mmol) is taken up in H₂SO₄ (150 mL, 90%) and heated to 70° C. for 3.5 h. Then the reaction mixture is cooled to 20° C., added dropwise to ice water, the precipitate is filtered off, washed with H₂O, dried and pyridine Z.5 (10.5 g, 95%) is obtained.

Pyridine Z.5 (2.00 g, 10.0 mmol) and iron filings (2.77 g, 49.6 mol) are taken up in EtOH/H₂O (100 mL, 1:1), combined with NH₄Cl (265 mg, 4.91 mmol) and heated to 60° C. for 1 h. The solvent is removed, the residue is taken up in DCM/MeOH (50 mL, 9:1), filtered through Celite, the solvent is eliminated again and pyridine Z.6 (1.57 g, 92%) is obtained.

Pyridine Z.6 (500 mg, 2.91 mmol) is taken up in triethylorthoformate (10 mL) and heated to 145° C. for 18 h. Then the reaction mixture is cooled to 20° C., the precipitate is filtered off, washed with Et₂O (10 mL), dried and azaquinazolone Z.7 (433 mg, 82%) is obtained.

Azaquinazolone Z.7 (200 mg, 1.10 mmol) is placed in toluene (5.0 mL), combined with N,N-diethylaniline (0.27 mL) and POCl₃ (0.88 mL) and heated to 110° C. for 4 h. The reaction mixture is cooled to 20° C., diluted with toluene (5 mL) and H₂O (5 mL), washed with NaOH (3×10 mL, 20%) and HCl (2×10 mL, 1 M), dried on Na₂SO₄, filtered, freed from the solvent and azaquinazoline D*.2 (165 mg, 75%) is obtained.

Azaquinazoline D*.2 (1.15 g, 5.75 mmol) is placed in DCM (5.0 mL), cooled to 0° C., combined with methylamine (3.5 mL, 7.19 mmol, 2 M in THF) and DIPEA (3.0 mL), the reaction mixture is heated to 20° C. and stirred for 1 h at 20° C. The solvent is removed, the residue is taken up in H₂O, the precipitate is filtered off, washed with H₂O and azaquinazoline D.2 (640 mg, 57%; HPLC-MS: MS (M+H)⁺=195; t_(Ret.)=1.85 min; method 1_BAS).

Method of Synthesising the Quinazolines D*.3 and D.3

Anthranilic acid ED.5 (1.00 g, 4.27 mmol) is placed in 2-methoxyethanol (2.0 mL), combined with formamidine acetate (890 mg, 8.55 mmol) and heated to 125° C. for 20 h. The reaction mixture is added to aqueous NH₃ (200 mL, 0.01 M), the precipitate is filtered off, dried and quinazolone Z.8 (817 mg, 79%) is obtained.

Quinazolone Z.8 (817 mg, 3.36 mmol) is combined with SOCl₂ (20 mL) and DMF (0.05 mL) and heated to 80° C. for 2 h. The solvent is removed and quinazoline D*.3 (879 mg, 100%) is obtained.

Quinazoline D*.3 (879 mg, 3.36 mmol) is combined with methylamine (30 mL, 2 M in THF) and stirred for 1 h at 20° C. The solvent is eliminated, the residue is purified by chromatography (35:65 to 80:20 in 12 min MeOH/H₂O) and quinoline D.3 (555 mg, 65%; HPLC-MS: MS (M+H)⁺=256/258; t_(Ret.)=1.86 min; method FECBM4) is obtained.

Method of Synthesising Quinazoline D.4

Aminoalcohol ED.6 (98 μL, 0.76 mmol) is placed in DMF, combined with K₂CO₃ (105 mg, 0.76 mmol) and stirred for 5 min at 20° C. Then quinazoline D*.4 (200 mg, 0.69 mmol) is added and the mixture is stirred for 30 min at 150° C. The solvent is removed and D.4 (24 mg, 10%; HPLC-MS: MS (M+H)⁺=358; t_(Ret.)=1.78 min; method LCMSBAS1) is obtained.

Compounds D.5-D.14 are prepared analogously to quinazolines D.1 to D.4 (Table 6):

MS (M + H)⁺; HPLC # Structure t_(Ret.) HPLC [min] method D.1 

M + H = 300; t_(Ret.) = 1.43 LCMSBAS1 D.2 

M + H = 195; t_(Ret.) = 1.85 1_BAS D.3 

M + H = 256/258; t_(Ret.) = 1.86 FECBM4 D.4 

M + H = 358; t_(Ret.) = 1.78 LCMSBAS1 D.5 

M + H = 239/241; t_(Ret.) = 1.98 FECBM4 D.6 

M + H = 239/241; t_(Ret.) = 1.15 M2-SB-218 D.7 

M + H = 252/254; t_(Ret.) = 1.95 LCMSBAS1 D.8 

M + H = 272/274; t_(Ret.) = 1.98 FECB6 D.9 

M + H = 256/258; t_(Ret.) = 1.86 FECBM4 D.10

M + H = 301; t_(Ret.) = 1.86 LCMSBAS1 D.11

M + H = 316; t_(Ret.) = 1.79 FECBM4 D.12

M + H = 332; t_(Ret.) = 1.83 LCMSBAS1 D.13

M + H = 346; t_(Ret.) = 1.87 LCMSBAS1 D.14

M + H = 201; t_(Ret.) = 1.85 LCMSBAS1

Method of Synthesising Quinoxaline D.15

Quinoxaline D*.5 (100 mg, 0.41 mmol) is placed in isopropanol (0.5 mL), mixed with aminopiperidinethanol ED.7 (296 mg, 2.05 mmol) and DIPEA (0.7 mL) and stirred for 24 h at 100° C. The solvent is removed, the residue is purified by chromatography (95:5 to 50:50 in 6 min H₂O/CH₃CN) and quinoxaline D.15 (46 mg, 32%) is obtained.

Compounds D.16-D.50 are prepared analogously to quinoxaline D.15 (Table 7):

MS (M + H)⁺; # Structure t_(Ret.) HPLC [min] HPLC method D.15

M + H = 351/353; t_(Ret.) = 1.57 FECB3 D.16

M + H = 309/311; t_(Ret.) = 2.08 LCMSBAS1 D.17

M + H = 309/311; t_(Ret.) = 2.11 LCMSBAS1 D.18

M + H = 295/297; t_(Ret.) = 2.07 LCMSBAS1 D.19

M + H = 323/325; t_(Ret.) = 2.13 LCMSBAS1 D.20

M + H = 238/240; t_(Ret.) = 1.98 LCMSBAS1 D.21

M + H = 252/254; t_(Ret.) = 2.08 LCMSBAS1 D.22

M + H = 293/295; t_(Ret.) = 1.84 LCMSBAS1 D.23

M + H = 307/309; t_(Ret.) = 2.03 LCMSBAS1 D.24

M + H = 310/312; t_(Ret.) = 2.16 LCMSBAS1 D.25

M + H = 312/314; t_(Ret.) = 2.18 LCMSBAS1 D.26

M + H = 321/323; t_(Ret.) = 1.70 LCMSBAS1 D.27

M + H = 321/323; t_(Ret.) = 1.58 LCMSBAS1 D.28

M + H = 335/337; t_(Ret.) = 1.60 LCMSBAS1 D.29

M + H = 347/349; t_(Ret.) = 1.63 LCMSBAS1 D.30

M + H = 307/309; t_(Ret.) = 1.70 LCMSBAS1 D.31

M + H = 337/339; t_(Ret.) = 1.93 LCMSBAS1 D.32

M + H = 306/308; t_(Ret.) = 2.01 LCMSBAS1 D.33

M + H = 307/309; t_(Ret.) = 1.31 LCMSBAS1 D.34

M + H = 335/337; t_(Ret.) = 1.75 LCMSBAS1 D.35

M + H = 347/349; t_(Ret.) = 1.77 LCMSBAS1 D.36

M + H = 321/323; t_(Ret.) = 1.76 LCMSBAS1 D.37

M + H = 321/323; t_(Ret.) = 1.76 LCMSBAS1 D.38

M + H = 266/268; t_(Ret.) = 1.81 LCMSBAS1 D.39

M + H = 322/324; t_(Ret.) = 1.56 LCMSBAS1 D.40

M + H = 365/367; t_(Ret.) = 1.35 LCMSBAS1 D.41

M + H = 351/353; t_(Ret.) = 1.31 LCMSBAS1 D.42

M + H = 322/324; t_(Ret.) = 1.34 LCMSBAS1 D.43

M + H = 322/324; t_(Ret.) = 1.70 LCMSBAS1 D.44

M + H = 391/393; t_(Ret.) = 1.67 LCMSBAS1 D.45

M + H = 444/446; t_(Ret.) = 1.75 LCMSBAS1 D.46

M + H = 349/351; t_(Ret.) = 1.52 LCMSBAS1 D.47

M + H = 307/309; t_(Ret.) = 1.63 LCMSBAS1 D.48

M + H = 353/355; t_(Ret.) = 1.40 LCMSBAS1 D.49

M + H = 353/355; t_(Ret.) = 1.40 LCMSBAS1 D.50

M + H = 363/365; t_(Ret.) = 1.31 LCMSBAS1

Method of Synthesising Quinoxaline D.51

Methylene piperidine ED.8 (243 mg, 1.23 mmol) is combined with 9-BBN (2.46 mL, 0.5 M in THF) and heated to 65° C. for 1 h. Then the mixture is cooled to 20° C., quinoxaline D*.5 (300 mg, 1.23 mmol), Pd(dppf) (50 mg, 10 mol %) and K₂CO₃ (195 mg, 1.41 mmol) are placed in DMF/H₂O (1.2 mL, 5:1) and slowly the freshly prepared boronate is added dropwise. The reaction mixture is heated to 60° C. for 2 h, cooled, combined with NaHCO₃ and extracted with DCM (3×10 mL). The solvent is removed, the residue is purified by chromatography (45:55 to 90:10 in 6 min CH₃CN/H₂O) and quinoxaline D.51 (250 mg, 50%) is obtained.

Method of Synthesising Quinoxaline D.52

Boric acid ester ED.9 (0.07 mL, 0.35 mmol), quinoxaline D*.5 (50 mg, 0.21 mmol), Pd(dppf) (16 mg, 10 mol %) and Cs₂CO₃ (0.12 mL, 0.67 mmol, 70% in H₂O) are placed in THF/NMP (10.6 mL, 2:1) and the reaction mixture is heated to 50° C. for 1 h. Then the reaction mixture is cooled to 20° C., combined with NaHCO₃ and extracted with DCM (3×10 mL). The solvent is removed, the residue is purified by chromatography (90:10 to 80:20 in 20 min hexane/EtOAc) and quinoxaline D.52 (31 mg, 61%) is obtained.

Method of Synthesising Quinoxaline D.53

Boric acid ester ED.10 (0.07 mL, 0.35 mmol), quinoxaline D*.5 (50 mg, 0.21 mmol), Pd(dppf) (16 mg, 10 mol %) and Cs₂CO₃ (0.12 mL, 0.67 mmol, 70% in H₂O) are placed in THF/NMP (10.6 mL, 2:1) and the reaction mixture is heated to 50° C. for 1 h. The reaction mixture is cooled to 20° C., combined with NaHCO₃ and extracted with DCM (3×10 mL). The solvent is removed, the residue is purified by chromatography (80:20 to 70:30 in 20 min hexane/EtOAc) and quinoxaline D.53 (35 mg, 65%) is obtained.

Method of Synthesising Quinoline D.54

Quinoline D*.6 (50 mg, 0.17 mmol) is placed in DCM (1.0 mL), combined with DIPEA (0.06 mL, 0.34 mmol) and piperidinone ED.11 (0.1 mL, 0.85 mmol) and stirred for 1 h at 20° C. Then CH₃COOH (0.48 mL) and NaBH(OAc)₃ (268 mg, 1.27 mmol) are added and the mixture is stirred for 3 h at 20° C. The solvent is removed, the residue is purified by chromatography (20:80 to 80:20 in 12 min CH₃CN/H₂O) and quinoline D.54 (50 mg, 92%; HPLC-MS: MS (M+H)⁺=320/322; t_(Ret.)=1.37 min; method FSUN2) is obtained.

Compounds D.55 and D.56 are prepared analogously to quinoline D.54 (Table 8):

MS (M + H)⁺; # Structure t_(Ret.) HPLC [min] HPLC method D.51

n.a. — D.52

n.a. — D.53

n.a. — D.54

n.a. — D.55

M + H = 334/336; t_(Ret.) = 1.21 FECS2 D.56

M + H = 364/366; t_(Ret.) = 1.26 FECS2

Method of Synthesising Quinoline D.57

Ethoxyacrylate ED.13 (6.4 mL, 44.3 mmol) is placed in MeOH (120 mL), combined with HCl (88 mL, 2M in H₂O) and heated to 100° C. Benzaldehyde ED.12 (4.00 g, 20.1 mmol) is placed in MeOH (120 mL), slowly added dropwise to the reaction mixture and the reaction mixture is heated to 100° C. for 4 h. Then it is made basic with NaHCO₃, the solvent is eliminated, the residue is purified by chromatography (90:10 to 40:60 in 15 min hexane/EtOAc) and quinoline D.57 (4.08 g, 51%; HPLC-MS: MS (M+H)⁺=266/268; t_(Ret)=1.50 min; method LCMSBAS1) is obtained.

Compounds D.58 and D.59 are prepared analogously to quinoline D.57 (Table 9):

MS (M + H)⁺; t_(Ret.) HPLC HPLC # Structure [min] method D.57

M + H = 266/268; t_(Ret.) = 1.50 LCMSBAS1 D.58

M + H = 280/282; t_(Ret.) = 1.52 LCMSBAS1 D.59

M + H = 298/300; t_(Ret.) = 1.49 1_FEC

Method of Synthesising Quinoline D.60

Quinoline D.58 (500 mg, 1.58 mmol) is placed in dioxane (5.0 mL), combined with LiOH (3.2 mL, 3.2 mmol, 1M in H₂O) and stirred for 20 min at 20° C. Then the mixture is diluted with H₂O, adjusted to pH=1 with HCl and the carboxylic acid Z.9 is filtered off.

The carboxylic acid Z.9 is taken up in DMF (0.5 mL) and stirred with SO₂Cl₂ (5.0 mL) for 40 min at 20° C. The solvent is removed and the acid chloride Z.10 (495 mg, 100%) is further reacted directly.

Dimethylamine (1.9 mL, 3.7 mmol, 2 M in THF) is placed in THF (10 mL), cooled to −10° C. and combined with acid chloride Z.10 (215 mg, 0.76 mmol). The reaction mixture is heated to 20° C. over 1 h, then diluted with H₂O (10 mL), extracted with DCM (3×20 mL), dried on MgSO₄, filtered, the solvent is eliminated and quinoline D.60 (185 mg, 84%; HPLC-MS: MS (M+H)⁺=293/295; t_(Ret.)=1.48 min; method LCMSBAS1) is obtained.

Compound D.61 is prepared analogously to quinoline D.60 (Table 10):

MS (M + H)⁺; t_(Ret.) HPLC HPLC # Structure [min] method D.60

M + H = 293/295; t_(Ret.) = 1.45 LCMSBAS1 D.61

M + H = 279/281; t_(Ret.) = 1.45 LCMSBAS1

Method of Synthesising Quinoline D*.7

Quinolinester D.57 (3.80 g, 9.46 mmol) is placed in THF (50 mL), cooled to −20° C. and combined with DIBAL-H (57.0 mL, 56.9 mmol, 1M in DCM). The reaction mixture is heated to 20° C. over 2 h, then it is diluted with H₂O, the solvent is eliminated, the residue is purified by chromatography (90:10 to 40:60 in 15 min hexane/EtOAc) and quinoline D*.7 (716 mg, 29%) is obtained.

Method of Synthesising Quinoline D*.8

Alcohol D*.7 (716 mg, 2.70 mmol) is placed in DCM (9 mL), combined with MnO₂ (705 mg, 8.12 mmol) and stirred for 2 d at 20° C. The reaction mixture is filtered through Celite, the solvent is eliminated and product D*.8 (577 mg, 63%) is obtained.

Method of Synthesising Quinoline D.62

Aldehyde D*.8 (82 mg, 0.35 mmol) is placed in DCM (1.5 mL), combined with amine ED.14 (0.18 mL, 1.39 mmol) and CH₃COOH (0.09 mL) and stirred for 10 min at 20° C. Then NaBH(OAc)₃ (110 mg, 0.52 mmol) is added, the mixture is stirred for 12 h at 20° C., the solvent is eliminated, the residue is purified by chromatography (20:80 to 80:20 in 15 min CH₃CN/H₂O) and quinoline D.62 (68 mg, 59%) is obtained.

Compounds D.63-D.67 are prepared analogously to quinoline D.62 (Table 11):

MS (M + H)⁺; # Structure t_(Ret.) HPLC [min] HPLC method D.62

M + H = 334; t_(Ret.) = 1.67 LCMSBAS1 D.63

M + H = 265/267; t_(Ret.) = 1.62 LCMSBAS1 D.64

M + H = 265/267; t_(Ret.) = 1.55 LCMSBAS1 D.65

M + H = 320/322; t_(Ret.) = 1.58 LCMSBAS1 D.66

M + H = 334/336; t_(Ret.) = 1.67 LCMSBAS1 D.67

M + H = 334/336; t_(Ret.) = 1.64 LCMSBAS1

Method of Synthesising Quinoline D.68

NaH (43 mg, 1.07 mmol, 60%) is placed in NMP (2.0 mL), combined with aminoalcohol ED.15 (0.17 mL, 0.91 mmol) and quinoline D*.9 (200 mg, 0.83 mmol) and stirred for 12 h at 20° C. Then the reaction mixture is diluted with H₂O (5 mL), extracted with DCM (3×5 mL), dried on MgSO₄, filtered, the solvent is eliminated and quinoline D.68 (255 mg, 90%; HPLC-MS: MS (M+H)⁺=309/311; t_(Ret.)=1.86 min; method LCMSBAS1) is obtained.

Compounds D.69-D.91-9 are prepared analogously to quinoline D.68 (Table 12):

MS (M + H)⁺; # Structure t_(Ret.) HPLC [min] HPLC method D-68

M + H = 309/311; t_(Ret.) = 1.86 LCMSBAS1 D.69

M + H = 321/323; t_(Ret.) = 1.77 LCMSBAS1 D.70

M + H = 322/324; t_(Ret.) = 1.92 LCMSBAS1 D.71

M + H = 238/240; t_(Ret.) = 1.61 AFEC D.72

M + H = 252/254; t_(Ret.) = 1.75 AFEC D.73

M + H = 266/268; t_(Ret.) = 1.82 AFEC D.74

M + H = 295/297; t_(Ret.) = 0.22 AFEC D.75

M + H = 296/298; t_(Ret.) = 1.86 LCMSBAS1 D.76

M + H = 364/366; t_(Ret.) = 0.21 AFEC D.77

M + H = 337/339; t_(Ret.) = 0.54 AFEC D.78

M + H = 325/327; t_(Ret.) = 0.18 AFEC D.79

M + H = 307/309; t_(Ret.) = 0.18 AFEC D.80

M + H = 322/324; t_(Ret.) = 1.85 AFEC D.81

M + H = 310/312; t_(Ret.) = 1.81 AFEC D.82

M + H = 321/323; t_(Ret.) = 0.26 AFEC D.83

M + H = 324/326; t_(Ret.) = 1.86 LCMSBAS1 D.84

M + H = 237/239; t_(Ret.) = 1.98; BFEC D.85

M + H = 263/265; t_(Ret.) = 2.10 BFEC D.86

M + H = 317/319; t_(Ret.) = 2.26 BFEC D.87

M + H = 294/296; t_(Ret.) = 1.50 BFEC D.88

M + H = 308/310; t_(Ret.) = 0.15 AFEC D.89

M + H = 304/306; t_(Ret.) = 1.63 AFEC D.90

M + H = 308/310; t_(Ret.) = 1.75 AFEC D.91

M + H = 343/345; t_(Ret.) = 2.24 AFEC D.91-1 

n.a. D.91-2 

M + H = 369; t_(Ret.) = 1.34 LCMSBAS1 D.91-3 

M + H = 369; t_(Ret.) = 1.34 LCMSBAS1 D.91-4 

M + H = 370; t_(Ret.) = 1.70 AFEC D.91-5 

M + H = 342; t_(Ret.) = 1.34 BFEC D.91-6 

M + H = 370; t_(Ret.) = 1.75 AFEC D.91-7 

n.a. D.91-8 

M + H = 342; t_(Ret.) = 1.94 AFEC D.91-9 

M + H = 369; t_(Ret.) = 1.88 LCMSBAS1 D.91-10

M + H = 321; t_(Ret.) = 0.29 AFEC

Method of Synthesising Quinoline D.91-11

Quinoline D.91-9 (100 mg, 0.23 mmol) is taken up in DMF (3 mL), combined with K₂CO₃ (94 mg, 1 mmol) and stirred for 5 min at RT. Then ED.15-1 (45 mg, 0.24 mmol) is added and the mixture is stirred for 12 h at RT. Then K₂CO₃ (94 mg, 1 mmol) and chloride ED.15-1 (45 mg, 0.24 mmol) are added once again and the mixture is stirred for a further 12 h at RT, then 48 h at 60° C. The reaction mixture is diluted with H₂O (5 mL), extracted with EtOAc (3×5 mL), dried on MgSO₄, filtered, the solvent is removed, the crude product is purified by chromatography (10:90 to 80:20 in 10 min CH₃CN/H₂O) and quinoline D.91-11 (HPLC-MS: MS (M+H)⁺=482; t_(Ret.)=1.36 min; method LCMSBAS1) is obtained.

Compounds D.91-12 and D.91-13 are prepared analogously to quinoline D.91-11 (Table 12a):

MS (M + H)⁺; t_(Ret.) HPLC HPLC # Structure [min] method D.91- 11

M + H = 482; t_(Ret.) = 1.36 LCMSBAS1 D.91- 12

M + H = 363; t_(Ret.) = 2.16 AFEC D.91- 13

M + H = 383; t_(Ret.) = 1.92 LCMSBAS1

Method of Synthesising Quinoline D*.10

Aniline ED.16 (5.00 g, 22.4 mmol) and cyanoacrylate ED.17 (3.86 g, 22.4 mmol) are placed in toluene (12 mL) and heated to 150° C. for 18 h. Then the reaction mixture is cooled to 20° C., the precipitate is filtered off, washed with diethyl ether (12 mL), dried, and intermediate Z.11 (6.46 g, 84%) is obtained.

Some of the intermediate Z.11 (1.54 g, 4.50 mmol) is taken up in Ph₂O (10 mL) and heated to 250° C. for 18 h. Then the reaction mixture is cooled to 20° C., the precipitate is filtered off, washed with diethyl ether (12 mL), dried and quinolinone Z.12 (930 mg, 70%) is obtained.

Quinolinone Z.12 (930 mg, 3.14 mmol) is taken up in POCl₃ (3.0 mL) and the mixture is heated to 160° C. for 5 h. The solvent is removed, the residue is combined with NaHCO₃ (10 mL) and ice water, the precipitate is filtered off, washed with H₂O (10 mL) and quinoline D*.10 (908 mg, 92%) is obtained.

Method of Synthesising Quinoline D*.11

Anthranilic acid ED.18 (5.06 g, 19.2 mmol) is stirred in conc. HCl (7.0 mL) for 12 h at 20° C. In a second round flask nitromethane (2.56 g, 42.0 mmol) is added dropwise to a mixture of ice (6.0 g, 333 mmol) and NaOH (2.53 g, 63.4 mmol), stirred for 1 h at 0° C., then heated to 20° C. over 1 h, then poured onto an ice/HCl mixture (5 g/7 mL) and combined with the aniline-HCl mixture. The reaction mixture is stirred for 12 h at 20° C., the precipitate is filtered off, washed with H₂O and dried.

The precipitate is taken up in acetic anhydride (35 mL), combined with KOAc (2.19 g, 22.3 mmol) and heated to 120° C. for 2 h. The solvent is removed and the residue is washed with glacial acetic acid and H₂O and dried.

The residue is taken up in POCl₃ (20 mL, 209 mmol) and heated to 120° C. for 40 min. The reaction mixture is evaporated down to one third, poured onto ice water, washed with H₂O, dried and quinoline D*.11 (4.0 g, 95%) is obtained.

Method of Synthesising Quinoline D.92

Quinoline D*.11 (1.00 g, 2.99 mmol) is placed in DMSO (0.5 mL), combined with ethylamine (202 mg, 4.49 mmol) and NEt₃ (1.81 g, 15.0 mmol) and stirred for 2 h at 20° C. and 4 h at 50° C. The precipitate is filtered off, washed with CH₃CN (5 mL), dried and quinoline D.92 (450 mg, 43%; HPLC-MS: MS (M+H)⁺=344; t_(Ret.)=1.58 min; method LCMSBAS1) is obtained.

Compounds D.93 and D.94 are prepared analogously to quinoline D.92 (Table 13):

MS (M + H)⁺; HPLC # Structure t_(Ret.) HPLC [min] method D.92

M + H = 344; t_(Ret.) = 1.58 LCMSBAS1 D.93

M + H = 330; t_(Ret.) = 1.61 LCMSBAS1 D.94

M + H = 358; t_(Ret.) = 1.67 LCMSBAS1

d) Synthesis of Compounds According to the Invention (1)

C and D are linked together by SONOGASHIRA reaction. The electron withdrawing groups EWG may be in particular halogen (chlorine, bromine, iodine), triflate or mesylate (cf. also reaction scheme C).

Method of Synthesising I-1

Iodide D.4 (24 mg, 0.07 mmol), propargylamide C.1 (24 mg, 0.08 mmol), Pd(PPh₃)₄ (1.5 mg, 10 mol %) and CuI (0.2 mg, 10 mol %) are placed in DMSO (0.3 mL), combined with DIPEA (0.07 mL) and stirred for 1 h at 40° C. The reaction mixture is mixed with water and DCM, the organic phase is separated off and extracted another 2× with water. Then the organic phase is dried, the solvent is eliminated in vacuo, the crude product is purified by chromatography (20:80 to 80:20 in 15 min CH₃CN/H₂O) and quinazoline I-1 (6 mg, 17%; HPLC-MS: MS (M+H)⁺=533; t_(Ret.)=1.85 min; method LCMSBAS1) is obtained.

Compounds I-2-I-8 may be prepared analogously to compound I-1 (Table 14):

MS (M + H)⁺; # Structure t_(Ret.) HPLC [min] HPLC method I-1

M + H = 533; t_(Ret.) = 1.85 LCMSBAS1 I-2

M + H = 462; t_(Ret.) = 1.78 LCMSBAS1 I-3

M + H = 474; t_(Ret.) = 1.72; LCMSBAS1 I-4

M + H = 462; t_(Ret.) = 1.44 LCMSBAS1 I-5

M + H = 495; t_(Ret.) = 1.70 LCMSBAS1 I-6

M + H = 495; t_(Ret.) = 1.57 LCMSBAS1 I-7

M + H = 476; t_(Ret.) = 1.90 LCMSBAS1 I-8

M + H = 533; t_(Ret.) = 1.85 LCMSBAS1

Method of Synthesising Quinoxaline I-9

Quinoxaline D.15 (46 mg, 0.13 mmol), propargylamide C.1 (50 mg, 0.16 mmol), Pd(dppf) (6 mg, 10 mol %) and CuI (6 mg, 20 mol %) are placed in DMSO (0.5 mL), combined with DIPEA (0.28 mL) and stirred for 3 h at 90° C. The solvent is removed, the residue is purified by chromatography (10:90 to 60:40 in 6 min CH₃CN/H₂O) and product I-9 (38 mg, 42%; HPLC-MS: MS (M+H)⁺=574; t_(Ret.)=1.69 min; method LCMSBAS1) is obtained.

Compounds I-10-I-65 are prepared analogously to quinoxaline I-9 (Table 15):

MS (M ± H)^(±); HPLC # Structure t_(Ret.) HPLC [min] method I-9

M + H = 574; t_(Ret.) = 1.69 LCMSBAS1 I-10

M + H = 532; t_(Ret.) = 1.85 LCMSBAS1 I-11

M + H = 532; t_(Ret.) = 1.88 LCMSBAS1 I-12

M + H = 518; t_(Ret.) = 1.78 LCMSBAS1 I-13

M + H = 546; t_(Ret.) = 1.96 LCMSBAS1 I-14

M + H = 461; t_(Ret.) = 1.67 LCMSBAS1 I-15

M + H = 475; t_(Ret.) = 1.84 LCMSBAS1 I-16

M + H = 530; t_(Ret.) = 1.79 LCMSBAS1 I-17

M + H = 533; t_(Ret.) = 1.99 LCMSBAS1 I-18

M + H = 535; t_(Ret.) = 1.99 LCMSBAS1 I-19

M + H = 544; t_(Ret.) = 1.77 LCMSBAS1 I-20

M + H = 544; t_(Ret.) = 1.80 LCMSBAS1 I-21

M + H = 544; t_(Ret.) = 1.83 LCMSBAS1 I-22

M + H = 558; t_(Ret.) = 1.85 LCMSBAS1 I-23

M − H = 568; t_(Ret.) = 1.92 LCMSBAS1 I-24

M + H = 530; t_(Ret.) = 1.80 LCMSBAS1 I-25

M + H = 560; t_(Ret.) = 2.08 LCMSBAS1 I-26

M − H = 527; t_(Ret.) = 2.08 LCMSBAS1 I-27

M + H = 530; t_(Ret.) = 1.87 LCMSBAS1 I-28

M + H = 558; t_(Ret.) = 1.92 LCMSBAS1 I-29

M + H = 570; t_(Ret.) = 2.04 LCMSBAS1 I-30

M + H = 557; t_(Ret.) = 1.94; LCMSBAS1 I-31

M + H = 543; t_(Ret.) = 1.86 LCMSBAS1 I-32

M + H = 537; t_(Ret.) = 1.68 LCMSBAS1 I-33

M + H = 544; t_(Ret.) = 1.85 LCMSBAS1 I-34

M + H = 544; t_(Ret.) = 1.77 LCMSBAS1 I-35

M + H = 489; t_(Ret.) = 1.88 LCMSBAS1 I-36

M + H = 545; t_(Ret.) = 1.56 LCMSBAS1 I-37

M + H = 588; t_(Ret.) = 1.62 LCMSBAS1 I-38

M + H = 545; t_(Ret.) = 2.08 LCMSBAS1 I-39

M + H = 545; t_(Ret.) = 1.68 LCMSBAS1 I-40

M + H = 614; t_(Ret.) = 1.79 LCMSBAS1 I-41

M + H = 573; t_(Ret.) = 1.76 LCMSBAS1 I-42

M + H = 667; t_(Ret.) = 1.94 LCMSBAS1 I-43

M + H = 572; t_(Ret.) = 1.93 LCMSBAS1 I-44

M + H = 530; t_(Ret.) = 1.96 LCMSBAS1 I-45

M + H = 576; t_(Ret.) = 1.87 LCMSBAS1 I-46

M + H = 557; t_(Ret.) = 2.08 LCMSBAS1 I-47

M + H = 576; t_(Ret.) = 1.87 LCMSBAS1 I-48

M + H = 617; t_(Ret.) = 1.77 LCMSBAS1 I-49

M + H = 587; t_(Ret.) = 1.88 LCMSBAS1 I-50

M + H = 587; t_(Ret.) = 1.85 LCMSBAS1 I-51

M + H = 571; t_(Ret.) = 2.09 LCMSBAS1 I-52

M + H = 601; t_(Ret.) = 1.98 LCMSBAS1 I-53

M + H = 588; t_(Ret.) = 2.02 LCMSBAS1 I-54

M + H = 586; t_(Ret.) = 1.89 LCMSBAS1 I-55

M + H = 599; t_(Ret.) = 1.85 LCMSBAS1 I-56

M + H = 586; t_(Ret.) = 1.71 LCMSBAS1 I-57

M − H = 583; t_(Ret.) = 1.76 LCMSBAS1 I-58

M − H = 597; t_(Ret.) = 1.85 LCMSBAS1 I-59

M + H = 607; t_(Ret.) = 1.70 LCMSBAS1 I-60

M + H = 614; t_(Ret.) = 1.95 LCMSBAS1 I-61

M + H = 678; t_(Ret.) = 1.90 LCMSBAS1 I-62

M + H = 667; t_(Ret.) = 2.10 LCMSBAS1 I-63

M − H = 595; t_(Ret.) = 1.63 LCMSBAS1 I-64

M + H = 625; t_(Ret.) = 1.73 LCMSBAS1 I-65

M + H = 660; t_(Ret.) = 1.86 LCMSBAS1

Method of Synthesising Quinoxaline I-66

Quinoxaline D.51 (250 mg, 0.62 mmol), propargylamide C.1 (205 mg, 0.68 mmol), Pd(dppf) (30 mg, 10 mol %) and CuI (26 mg, 20 mol %) are placed in DMSO (2.0 mL), combined with DIPEA (1.2 mL) and stirred for 3 h at 50° C. The solvent is removed, the residue is purified by chromatography (30:70 to 95:5 in 6 min CH₃CN/H₂O) and the protected quinoxaline Boc-I-66 (372 mg, 88%) is obtained.

Boc-I-66 (372 mg, 0.59 mmol) is placed in DCM (10.0 mL), combined with TFA (1.0 mL) and stirred for 1 h at 20° C. It is made basic with NaHCO₃ (10 mL), extracted with DCM (3×20 mL), the solvent is removed and product I-66 (260 mg, 83%; HPLC-MS: MS (M+H)⁺=529; t_(Ret.)=2.00 min; method LCMSBAS1) is obtained.

Method of Synthesising Quinoxaline I-67

Quinoxaline I-66 (35 mg, 0.07 mmol) is placed in DMA (0.8 mL), combined with formaldehyde (5.9 μL, 37%, 0.07 mmol) and acetic acid (4 μL, 0.07 mmol) and stirred for 1 h at 20° C. Then NaBH(OAc)₃ (16 mg, 0.07 mmol) is added and the mixture is stirred for another 12 h at 20° C. It is diluted with MeOH (10 mL), then the solvent is eliminated, it is purified by chromatography (20:80 to 80:20 in 6 min CH₃CN/H₂O) and quinoxaline I-67 (16 mg, 45%; HPLC-MS: MS (M+H)⁺=543; t_(Ret.)=1.91 min; method LCMSBAS1) is obtained.

Compounds I-68 and I-69 are prepared analogously to quinoxaline I-67 (Table 16):

MS (M + H)⁺; HPLC # Structure t_(Ret.) HPLC [min] method I-66

M + H = 529; t_(Ret.) = 2.00 LCMSBAS1 I-67

M + H = 543; t_(Ret.) = 1.91 LCMSBAS1 I-68

M + H = 486; t_(Ret.) = 2.09 LCMSBAS1 I-69

M + H = 472; t_(Ret.) = 2.06 LCMSBAS1

Method of Synthesising Quinoline I-70

Quinoline D.54 (50 mg, 0.18 mmol), propargylamide C.1 (55 mg, 0.16 mmol), Pd(dppf) (7 mg, 10 mol %) and CuI (7 mg, 20 mol %) are placed in DMSO (0.40 mL), combined with DIPEA (0.31 mL) and stirred for 3 h at 90° C. The solvent is removed, the residue is purified by chromatography (20:80 to 80:20 in 6 min CH₃CN/H₂O) and quinoline I-70 (28 mg, 28%; HPLC-MS: MS (M+H)⁺=543; t_(Ret.)=1.80 min; method LCMSBAS1) is obtained.

Compounds I-71-I-78 are prepared analogously to quinoline I-70 (Table 17):

MS (M + H)⁺; HPLC # Structure t_(Ret.) HPLC [min] method I-70

M + H = 543; t_(Ret.) = 1.80 LCMSBAS1 I-71

M + H = 557; t_(Ret.) = 1.91 LCMSBAS1 I-72

M + H = 556; t_(Ret.) = 1.97 LCMSBAS1 I-73

M + H = 587; t_(Ret.) = 1.86 LCMSBAS1 I-74

M + H = 586; t_(Ret.) = 1.97 LCMSBAS1 I-75

M + H = 570; t_(Ret.) = 2.07 LCMSBAS1 I-76

M + H = 568; t_(Ret.) = 1.83 LCMSBAS1 I-77

M + H = 616; t_(Ret.) = 1.80 LCMSBAS1 I-78

M + H = 600; t_(Ret.) = 1.98 LCMSBAS1

Method of Synthesising Quinoline I-79

Quinoline D.59 (60 mg, 0.17 mmol), propargylamide C.1 (58 mg, 0.19 mmol), Pd(PPh)₃ (20 mg, 10 mol %) and CuI (3 mg, 10 mol %) are placed in DMSO (1.0 mL), combined with DIPEA (0.11 mL) and stirred for 30 min at 100° C. The solvent is removed, the residue is purified by chromatography (20:80 to 80:20 in 6 min CH₃CN/H₂O) and quinoline I-79 (49 mg, 54%; HPLC-MS: MS (M+H)⁺=521; t_(Ret.)=2.21 min; method LCMSBAS1) is obtained.

Compounds I-80-I-87 are prepared analogously to quinoline I-79 (Table 18):

MS (M ± H)^(±); HPLC # Structure t_(Ret.) HPLC [min] method I-79

M + H = 521; t_(Ret.) = 2.21 LCMSBAS1 I-80

M + H = 431; t_(Ret.) = 1.72 LCMSBAS1 I-81

M + H = 507; t_(Ret.) = 2.09 LCMSBAS1 I-82

M + H = 503; t_(Ret.) = 1.89 LCMSBAS1 I-83

M + H = 489; t_(Ret.) = 1.15 LCMSBAS1 I-84

M + H = 502; t_(Ret.) = 1.61 LCMSBAS1 I-85

M + H = 516; t_(Ret.) = 1.66 LCMSBAS1 I-86

M + H = 447; t_(Ret.) = 1.15 LCMSBAS1 I-87

M + H = 530; t_(Ret.) = 1.86 LCMSBAS1

Method of Synthesising Quinoline I-88

Quinoline D.68 (61 mg, 0.20 mmol), propargylamide C.1 (83 mg, 0.21 mmol), Pd(PPh)₃ (16 mg, 10 mol %) and CuI (3 mg, 10 mol %) are placed in DMSO (1.0 mL), combined with DEA (0.1 mL) and stirred for 20 min at 80° C. The solvent is removed, the residue is purified by chromatography (99:1 to 80:20 in 6 min DCM/MeOH) and quinoline I-88 (18 mg, 17%; HPLC-MS: MS (M+H)⁺=532; t_(Ret.)=1.84 min; method LCMSBAS1) is obtained.

Compounds I-89-I-125.23 are prepared analogously to quinoline I-88 (Table 19):

MS (M + H)⁺; HPLC # Structure t_(Ret.) HPLC [min] method I-88

M + H = 532; t_(Ret.) = 1.84 LCMSBAS1 I-89

M + H = 545; t_(Ret.) = 1.90 LCMSBAS1 I-90

M + H = 474; t_(Ret.) = 1.81 LCMSBAS1 I-91

M + H = 461; t_(Ret.) = 1.77 LCMSBAS1 I-92

M + H = 460; t_(Ret.) = 1.85 LCMSBAS1 I-93

M + H = 531; t_(Ret.) = 1.76 LCMSBAS1 I-94

M + H = 474; t_(Ret.) = 1.79 LCMSBAS1 I-95

M + H = 475; t_(Ret.) = 1.71 LCMSBAS1 I-96

M + H = 486; t_(Ret.) = 1.86 LCMSBAS1 I-97

M + H = 489; t_(Ret.) = 1.79 LCMSBAS1 I-98

M + H = 517; t_(Ret.) = 1.67 LCMSBAS1 I-99

M + H = 518; t_(Ret.) = 1.60 LCMSBAS1 I-100

M + H = 587; t_(Ret.) = 1.75 LCMSBAS1 I-101

M + H = 557; t_(Ret.) = 1.82 LCMSBAS1 I-102

M + H = 560; t_(Ret.) = 2.08 LCMSBAS1 I-103

M + H = 559; t_(Ret.) = 2.14 LCMSBAS1 I-104

M + H = 548; t_(Ret.) = 1.69 LCMSBAS1 I-105

M + H = 547; t_(Ret.) = 1.76 LCMSBAS1 I-106

M + H = 530; t_(Ret.) = 1.77 LCMSBAS1 I-107

M + H = 529; t_(Ret.) = 1.84 LCMSBAS1 I-108

M + H = 545; t_(Ret.) = 1.94 LCMSBAS1 I-109

M + H = 544; t_(Ret.) = 2.00 LCMSBAS1 I-110

M + H = 532; t_(Ret.) = 1.98 LCMSBAS1 I-111

M + H = 544; t_(Ret.) = 1.78 LCMSBAS1 I-112

M + H = 543; t_(Ret.) = 1.86 LCMSBAS1 I-113

M + H = 530; t_(Ret.) = 1.74 LCMSBAS1 I-114

M + H = 529; t_(Ret.) = 1.77 LCMSBAS1 I-115

M + H = 486; t_(Ret.) = 1.84 LCMSBAS1 I-116

M + H = 485; t_(Ret.) = 1.91 LCMSBAS1 I-117

M + H = 517; t_(Ret.) = 1.74 LCMSBAS1 I-118

M + H = 516; t_(Ret.) = 1.82 LCMSBAS1 I-119

M + H = 531; t_(Ret.) = 1.86 LCMSBAS1 I-120

M + H = 530; t_(Ret.) = 1.86 LCMSBAS1 I-121

M + H = 531; t_(Ret.) = 1.86 LCMSBAS1 I-122

M + H = 530; t_(Ret.) = 1.89 LCMSBAS1 I-123

M + H = 544; t_(Ret.) = 1.91 LCMSBAS1 I-124

M + H = 545; t_(Ret.) = 2.01 LCMSBAS1 I-125

M + H = 561; t_(Ret.) = 0.24 LCMSBAS1 I-125.1

M + H = 575; t_(Ret.) = 1.49 LCMSBAS1 I-125.2

M + H = 549; t_(Ret.) = 1.56 LCMSBAS1 I-125.3

M + H = 546; t_(Ret.) = 1.93 LCMSBAS1 I-125.4

M + H = 560; t_(Ret.) = 1.75 LCMSBAS1 I-125.5

M + H = 560; t_(Ret.) = 1.45 LCMSBAS1 I-125.6

M + H = 545; t_(Ret.) = 1.39 LCMSBAS1 I-125.7

M + H = 517; t_(Ret.) = 1.31 LCMSBAS1 I-125.8

M + H = 544; t_(Ret.) = 1.48 LCMSBAS1 I-125.9

M + H = 561; t_(Ret.) = 1.45 LCMSBAS1 I-125.10

M + H = 557; t_(Ret.) = 2.11 LCMSBAS1 I-125.11

M + H = 575; t_(Ret.) = 1.49 LCMSBAS1 I-125.12

M + H = 561; t_(Ret.) = 1.43 LCMSBAS1 I-125.13

M + H = 560; t_(Ret.) = 2.04 LCMSBAS1 I-125.14

M + H = 546; t_(Ret.) = 2.10 LCMSBAS1 I-125.15

M + H = 504; t_(Ret.) = 1.83 LCMSBAS1 I-125.16

M + H = 574; t_(Ret.) = 1.84 LCMSBAS1 I-125.17

M + H = 575; t_(Ret.) = 1.60 LCMSBAS1 I-125.18

M + H = 589; t_(Ret.) = 1.51 LCMSBAS1 I-125.19

M + H = 674; t_(Ret.) = 1.45 LCMSBAS1 I-125.20

M + H = 688; t_(Ret.) = 1.49 LCMSBAS1 I-125.21

M + H = 605; t_(Ret.) = 1.53 LCMSBAS1 I-125.22

M + H = 585; t_(Ret.) = 2.16 LCMSBAS1 I-125.23

M + H = 543; t_(Ret.) = 1.94 LCMSBAS1

Method of Synthesising Quinoline I-126

Quinoline D.92 (350 mg, 1.02 mmol), propargylamide C.1 (371 mg, 1.22 mmol), Pd(PPh)₃ (60 mg, 10 mol %) and CuI (2 mg, 5 mol %) are placed in DMSO (1.0 mL), combined with DIPEA (0.54 mL) and stirred for 30 min at 50° C. The solvent is removed, the residue is taken up in H₂O (5 mL), extracted with DCM (3×5 mL), dried on MgSO₄, filtered, the solvent is removed, the residue is purified by chromatography (95:5 to 40:60 in 6 min H₂O/MeOH) and product I-126 (306 mg, 60%; HPLC-MS: MS (M+H)⁺=519; t_(Ret.)=1.88 min; method LCMSBAS1) is obtained.

Compounds I-127 and I-128 are prepared analogously to quinoline I-126 (Table 20):

MS (M + H)⁺; HPLC # Structure t_(Ret.) HPLC [min] method I-126

M + H = 519; t_(Ret.) = 1.88 LCMSBAS1 I-127

M + H = 505; t_(Ret.) = 1.76 LCMSBAS1 I-128

M + H = 533; t_(Ret.) = 1.97 LCMSBAS1

e) Synthesis of Quinazoline, Quinoxaline and Quinoline Compounds E

C and D* are linked by SONOGASHIRA reaction. Electron-withdrawing groups EWG that may be used include in particular halogen (chlorine, bromine, iodine), triflate or mesylate (cf. also reaction scheme C).

Method of Synthesising Quinazoline E.1

Iodide D*.4 (1.60 g, 5.00 mmol), propargylamide C.1 (1.71 g, 5.50 mmol), Pd(PPh₃)₄ (117 mg, 10 mol %) and CuI (20 mg, 10 mol %) are placed in DMSO (20 mL), combined with DIPEA (5 mL) and stirred for 3 h at 40° C. The reaction mixture is combined with water and DCM, the organic phase is separated off and extracted another 2× with water. Then the organic phase is dried, the solvent is eliminated in vacuo, the crude product is purified by chromatography and quinazoline E.1 (2.12 g, 46%; HPLC-MS: MS (M−H)⁻=464; t_(Ret.)=1.93 min; method LCMSBAS1) is obtained.

Method of Synthesising Quinoline E.2

Quinoline D*.12 (50 mg, 0.18 mmol), propargylamide C.1 (55 mg, 0.16 mmol), Pd(dppf) (7 mg, 10 mol %) and CuI (7 mg, 20 mol %) are placed in DMSO (0.40 mL), combined with DIPEA (0.31 mL) and stirred for 3 h at 90° C. The solvent is removed, the residue is purified by chromatography (20:80 to 80:20 in 6 min CH₃CN/H₂O) and quinoline E.2 (28 mg, 28%) is obtained.

Method of Synthesising Quinoline E.3

Quinoline D*.9 (1.00 g, 4.12 mmol), propargylamide C.1 (1.50 g, 4.95 mmol), Pd(PPh)₃ (238 mg, 10 mol %) and CuI (32 mg, 5 mol %) are placed in DMSO (10.0 mL), combined with DIPEA (7.7 mL) and stirred for 2 h at 50° C. The solvent is removed, the residue is purified by chromatography (95:5 to 40:60 in 6 min H₂O/MeOH) and quinoline E.3 (1.51 g, 79% HPLC-MS: MS (M+H)⁺=465; t_(Ret.)=2.14 min; method FECB6) is obtained.

Method of Synthesising Quinoline E.4

Quinoline D*.10 (100 mg, 0.32 mmol), propargylamide C.1 (115 mg, 0.38 mmol), Pd(PPh)₃ (18 mg, 10 mol %) and CuI (3 mg, 5 mol %) are placed in DMSO (1.0 mL), combined with DIPEA (0.29 mL) and stirred for 3 h at 20° C. The solvent is removed, the residue is taken up in H₂O (5 mL), extracted with DCM (3×5 mL), dried on MgSO₄, filtered, the solvent is removed and quinoline E.4 (61 mg, 39%) is obtained.

f) Synthesis of Other Compounds (1) According to the Invention

Cf. remarks relating to reaction scheme C.

Method of Synthesising II-1

Quinazoline E.1 (300 mg, 0.23 mmol) is placed in DMSO (2 mL), combined with NEt₃ (116 mg, 0.96 mmol) and then added dropwise to methylamine (0.65 mL, 1.3 mL). The reaction mixture is stirred for 2 h at 20° C., freed from the solvent, the crude product is purified by chromatography (95:5 to 40:60 in 6 min H₂O/MeOH) and quinazoline II-1 (115 mg, 78%; HPLC-MS: MS (M+H)⁺=461; t_(Ret.)=1.55 min; method LCMSBAS1) is obtained.

Quinazolines II-2-II-63 are prepared analogously to quinazoline II-1 (Table 21):

MS (M ± H)^(±); HPLC # Structure t_(Ret.) HPLC [min] method II-1

M + H = 461; t_(Ret.) = 1.55 LCMSBAS1 II-2

M + H = 516; t_(Ret.) = 1.58 LCMSBAS1 II-3

M + H = 565; t_(Ret.) = 1.98 LCMSBAS1 II-4

M + H = 475; t_(Ret.) = 1.65 LCMSBAS1 II-5

M + H = 551; t_(Ret.) = 1.94 LCMSBAS1 II-6

M + H = 541; t_(Ret.) = 1.81 LCMSBAS1 II-7

M + H = 552; t_(Ret.) = 1.68 LCMSBAS1 II-8

M + H = 611; t_(Ret.) = 1.82 LCMSBAS1 II-9

M + H = 516; t_(Ret.) = 1.52 LCMSBAS1 II-10

M + H = 518; t_(Ret.) = 1.64 LCMSBAS1 II-11

M + H = 555; t_(Ret.) = 1.56 LCMSBAS1 II-12

M + H = 557; t_(Ret.) = 1.89 LCMSBAS1 II-13

M + H = 567; t_(Ret.) = 1.74 LCMSBAS1 II-14

M + H = 519; t_(Ret.) = 1.67 LCMSBAS1 II-15

M + H = 565; t_(Ret.) = 1.99 LCMSBAS1 II-16

M + H = 565; t_(Ret.) = 1.82 LCMSBAS1 II-17

M + H = 594; t_(Ret.) = 1.70 LCMSBAS1 II-18

M + H = 581; t_(Ret.) = 1.90 LCMSBAS1 II-19

M + H = 517; t_(Ret.) = 2.08 LCMSBAS1 II-20

M + H = 501; t_(Ret.) = 1.76 LCMSBAS1 II-21

M + H = 531; t_(Ret.) = 1.65 LCMSBAS1 II-22

M + H = 543; t_(Ret.) = 2.06 LCMSBAS1 II-23

M + H = 620; t_(Ret.) = 2.02 LCMSBAS1 II-24

M + H = 574; t_(Ret.) = 1.57 LCMSBAS1 II-25

M + H = 558; t_(Ret.) = 1.74 LCMSBAS1 II-26

M + H = 430; t_(Ret.) = 1.68 LCMSBAS1 II-27

M + H = 500; t_(Ret.) = 1.83 LCMSBAS1 II-28

M + H = 531; t_(Ret.) = 2.00 LCMSBAS1 II-29

M + H = 543; t_(Ret.) = 1.75 LCMSBAS1 II-30

M + H = 557; t_(Ret.) = 1.58 LCMSBAS1 II-31

M + H = 516; t_(Ret.) = 1.59 LCMSBAS1 II-32

M + H = 532; t_(Ret.) = 1.79 LCMSBAS1 II-33

M + H = 517; t_(Ret.) = 1.52 LCMSBAS1 II-34

M + H = 518; t_(Ret.) = 1.65 LCMSBAS1 II-35

M + H = 503; t_(Ret.) = 1.31 LCMSBAS1 II-36

M + H = 530; t_(Ret.) = 1.73 LCMSBAS1 II-37

M + H = 520; t_(Ret.) = 1.51 LCMSBAS1 II-38

M + H = 543; t_(Ret.) = 1.77 LCMSBAS1 II-39

M + H = 557; t_(Ret.) = 1.83 LCMSBAS1 II-40

M + H = 557; t_(Ret.) = 1.82 LCMSBAS1 II-41

M + H = 544; t_(Ret.) = 1.81 LCMSBAS1 II-42

M + H = 428; t_(Ret.) = 1.32 LCMSBAS1 II-43

M + H = 537/539; t_(Ret.) = 2.16 LCMSBAS1 II-44

M + H = 634; t_(Ret.) = 2.06 LCMSBAS1 II-45

M + H = 580; t_(Ret.) = 2.05 LCMSBAS1 II-46

M + H = 601; t_(Ret.) = 1.89 LCMSBAS1 II-47

M + H = 571; t_(Ret.) = 1.95 LCMSBAS1 II-48

M + H = 537; t_(Ret.) = 1.93 LCMSBAS1 II-49

M + H = 549; t_(Ret.) = 1.75 LCMSBAS1 II-50

M + H = 531; t_(Ret.) = 1.64 LCMSBAS1 II-51

M + H = 414; t_(Ret.) = 1.44 LCMSBAS1 II-52

M + H = 580; t_(Ret.) = 2.00 LCMSBAS1 II-53

M + H = 443; t_(Ret.) = 1.52 LCMSBAS1 II-54

M + H = 516; t_(Ret.) = 2.02 LCMSBAS1 II-55

M + H = 480; t_(Ret.) = 1.99 LCMSBAS1 II-56

M + H = 496; t_(Ret.) = 1.79 LCMSBAS1 II-57

M + H = 547; t_(Ret.) = 1.84 LCMSBAS1 II-58

M + H = 495; t_(Ret.) = 1.88 LCMSBAS1 II-59

M + H = 491; t_(Ret.) = 1.86 LCMSBAS1 II-60

M + H = 474; t_(Ret.) = 1.73 LCMSBAS1 II-61

M + H = 477; t_(Ret.) = 1.47 LCMSBAS1 II-62

M + H = 491; t_(Ret.) = 1.60 LCMSBAS1 II-63

M + H = 452; t_(Ret.) = 1.48 LCMSBAS1

Method of Synthesising II-64

Quinazoline E.1 (100 mg, 0.19 mmol), boric acid ED.19 (163 mg, 0.55 mmol), K₂CO₃ (128 mg, 0.92 mmol) and Pd(dppf) (15 mg, 10 mol %) are placed in THF/NMP (3 mL, 2:1) and the reaction mixture is stirred for 3 h at 100° C. and for 12 h at 20° C. Then HCl (1 mL, 4M in dioxane) is added, the mixture is heated to 50° C. for 30 min, freed from the solvent, the crude product is purified by chromatography (95:5 to 40:60 in 6 min H₂O/MeOH) and quinazoline II-64 (30 mg, 33%; HPLC-MS: MS (M+H)⁺=498; t_(Ret.)=1.55 min; method LCMSBAS1) is obtained.

Quinazolines II-65-II-67 are prepared analogously to quinazoline II-64 (Table 22):

MS (M ± H)^(±); HPLC # Structure t_(Ret.) HPLC [min] method II-64

M + H = 498; t_(Ret.) = 1.55 LCMSBAS1 II-65

M + H = 508; t_(Ret.) = 1.88 LCMSBAS1 II-66

M + H = 446; t_(Ret.) = 1.64 LCMSBAS1 II-67

M + H = 513; t_(Ret.) = 1.63 LCMSBAS1

Method of Synthesising Quinoline II-68

Quinoline E.2 (60 mg, 0.13 mmol) is placed in DMF, combined with HATU (58 mg, 0.15 mmol) and DIPEA (0.09 mL) and stirred for 10 min at 20° C. Then amine ED.20 (0.04 mL, 0.32 mmol) is added and the mixture is stirred for 12 h at 20° C. The solvent is removed, the residue is purified by chromatography (20:80 to 80:20 in 15 min CH₃CN/H₂O) and quinoline II-68 (28 mg, 28%; HPLC-MS: MS (M+H)⁺=559; t_(Ret.)=1.68 min; method LCMSBAS1) is obtained.

Compounds II-69-II-87 are prepared analogously to quinoline II-68 (Table 23):

MS (M ± H)^(±); HPLC # Structure t_(Ret.) HPLC [min] method II-68

M + H = 559; t_(Ret.) = 1.68 LCMSBAS1 II-69

M + H = 502; t_(Ret.) = 1.61 LCMSBAS1 II-70

M + H = 516; t_(Ret.) = 1.66 LCMSBAS1 II-71

M + H = 530; t_(Ret.) = 1.79 LCMSBAS1 II-72

M − H = 486; t_(Ret.) = 1.72 LCMSBAS1 II-73

M − H = 512; t_(Ret.) = 1.66 LCMSBAS1 II-74

M + H = 571; t_(Ret.) = 1.77 LCMSBAS1 II-75

M + H = 488; t_(Ret.) = 1.56 LCMSBAS1 II-76

M + H = 502; t_(Ret.) = 1.65 LCMSBAS1 II-77

M + H = 516; t_(Ret.) = 1.71 LCMSBAS1 II-78

M + H = 571; t_(Ret.) = 1.68 LCMSBAS1 II-79

M + H = 573; t_(Ret.) = 1.81 LCMSBAS1 II-80

M + H = 571; t_(Ret.) = 1.71 LCMSBAS1 II-81

M + H = 543; t_(Ret.) = 1.60 LCMSBAS1 II-82

M + H = 544; t_(Ret.) = 1.61 LCMSBAS1 II-83

M + H = 543; t_(Ret.) = 1.50 LCMSBAS1 II-84

M + H = 557; t_(Ret.) = 1.60 LCMSBAS1 II-85

M + H = 601; t_(Ret.) = 1.64 LCMSBAS1 II-86

M + H = 502; t_(Ret.) = 1.61 LCMSBAS1 II-87

M + H = 557; t_(Ret.) = 1.65 LCMSBAS1

Method of Synthesising Quinoline II-88

Quinoline E.3 (100 mg, 0.22 mmol), boric acid ester ED.21 (189 mg, 0.65 mmol), Pd(dppf) (17 mg, 10 mol %) and K₂CO₃ (149 mg, 1.07 mmol) are placed in THF/NMP (3.0 mL, 2:1) and stirred for 1 h at 100° C. Then the reaction mixture is diluted with H₂O (5 mL), extracted with DCM (3×5 mL), dried on MgSO₄, filtered and the solvent is eliminated. The residue is taken up in DCM (1.0 mL), combined with TFA (2.0 mL) and stirred for 12 h at 20° C. The reaction mixture is made basic with NaHCO₃ (5 mL), extracted with DCM (3×5 mL), dried on MgSO₄, filtered, the solvent is eliminated and the residue is purified by chromatography (95:5 to 40:60 in 6 min H₂O/MeOH) and quinoline II-88 (17 mg, 16%; HPLC-MS: MS (M+H)⁺=496; t_(Ret.)=1.78 min; method LCMSBAS1) is obtained.

Compounds II-89-II-93 are prepared analoqously to quinoline II-88 (Table 24):

MS (M + H)⁺; HPLC- # Structure t_(Ret.) HPLC [min] method II-88

M + H = 496; t_(Ret.) = 1.78 LCMSBAS1 II-89

M + H = 497; t_(Ret.) = 1.63 LCMSBAS1 II-90

M + H = 512; t_(Ret.) = 1.73 LCMSBAS1 II-91

M + H = 512; t_(Ret.) = 1.72 LCMSBAS1 II-92

M + H = 445; t_(Ret.) = 1.81 LCMSBAS1 II-93

M + H = 511; t_(Ret.) = 1.66 LCMSBAS1

Method of Synthesising Quinoline II-94

Quinoline E.4 (30 mg, 0.06 mmol) is combined with dimethylamine (0.31 mL, 0.61 mmol, 2 M in THF), DIPEA (16 μL) is added and the mixture is stirred for 1 h at 20° C. The solvent is eliminated, the residue is purified by chromatography (95:5 to 40:60 in 6 min H₂O/MeOH) and quinoline II-94 (17 mg, 16%; HPLC-MS: MS (M+H)⁺=498; t_(Ret.)=1.88 min; method LCMSBAS1) is obtained.

Compounds II-95-II-106 are prepared analogously to quinoline II-94 (Table 25):

MS (M + H)⁺; HPLC # Structure t_(Ret.) HPLC [min] method II-94 

M + H = 498; t_(Ret.) = 1.88 LCMSBAS1 II-95 

M + H = 566; t_(Ret.) = 2.21 LCMSBAS1 II-96 

M + H = 574; t_(Ret.) = 2.08 LCMSBAS1 II-97 

M + H = 566; t_(Ret.) = 2.19 LCMSBAS1 II-98 

M + H = 574; t_(Ret.) = 2.11 LCMSBAS1 II-99 

M + H = 580; t_(Ret.) = 2.27 LCMSBAS1 II-100

M + H = 526; t_(Ret.) = 2.06 LCMSBAS1 II-101

M + H = 526; t_(Ret.) = 2.04 LCMSBAS1 II-102

M + H = 560; t_(Ret.) = 2.00 LCMSBAS1 II-103

M + H = 512; t_(Ret.) = 1.97 LCMSBAS1 II-104

M + H = 512; t_(Ret.) = 1.94 LCMSBAS1 II-105

M + H = 484; t_(Ret.) = 1.78 LCMSBAS1 II-106

M + H = 588; t_(Ret.) = 2.13 LCMSBAS1 g) Method of Synthesising Quinazolines F (with Alkenyl Linkers)

In order to incorporate alkenyl linkers L the components D are first of all reacted with protected allylamines B in a HECK reaction to obtain the amine intermediates F. After the reaction of B with D the product obtained still contains the protective group PG, which is cleaved. The protective group PG used may be any of the amino protecting groups known in organic synthesis.

Method of Synthesising Quinazoline F.1

Quinazoline D*.13 (3.17 g, 13.0 mmol) is placed in DCM/MeCN (6 mL, 2:1), combined with DIPEA (0.33 mL) and methylamine (0.81 mL, 2 M in THF) and stirred for 1.5 h at 20° C. Then the solvent is removed, the residue is taken up in H₂O (15 mL), filtered off, washed with H₂O (3×15 mL) and Et₂O (3 mL), dried in vacuo and quinazoline D.95 (2.93 g, 95%; HPLC-MS: MS (M+H)⁺=238; t_(Ret.)=1.13 min; method LCMSBAS1) is obtained.

Quinazoline D.95 (1.19 g, 5.00 mmol), Pd(OAc)₂ (112 mg, 10 mol %) and tri(o-tolyl)phosphine (311 mg, 20 mol %) are placed in CH₃CN/NMP (12 mL, 5:1), combined with allylamine B.2 (1.59 g, 6.00 mmol) and then with DIPEA (1.8 mL) and heated to 110° C. for 1.5 h. The reaction mixture is filtered, then H₂O (50 mL) is added, the mixture is extracted with DCM (3×30 mL), dried on Na₂SO₄, filtered, freed from the solvent, the residue is purified by chromatography (97:3 to 82:18 in 6 min DCM/MeOH) and quinazoline Z.13 (415 mg, 90%; HPLC-MS: MS (M+H)⁺=415; t_(Ret.)=1.92 min; method LCMSBAS1) is obtained.

Quinazoline Z.13 (2.06 g, 5.00 mmol) is taken up in HCl (10 mL, 4M in dioxane) and stirred for 24 h at 20° C. The precipitate is filtered off, freed from the solvent and quinazoline F.1 (1.31 g, 70%; HPLC-MS: MS (M+H)⁺=215; t_(Ret.)=1.08 min; method LCMSBAS1) is obtained.

h) Synthesis of Quinazolines (1) According to the Invention with Alkenyl Linkers

Amide couplings which are supported in the first reaction step by coupling reagents such as for example DCC, DIC, TBTU, HATU, EDC or the like are used for the amide linking of the acids A and amines F.

Method of Synthesising Quinazoline III-1

Carboxylic acid A.46 (22 mg, 0.07 mmol) is placed in DMSO (0.2 mL), combined with DIPEA (56 μL) and HATU (40 mg, 0.10 mmol) and stirred for 10 min at 20° C. Then quinazoline F.1 (30 mg, 0.08 mmol) is added and the mixture is stirred for 3 h at 20° C. The solvent is eliminated, the residue is purified by chromatography (97:3 to 82:18 in 6 min H₂O/MeOH) and quinazoline III-1 (21 mg, 60%; HPLC-MS: MS (M+H)⁺=509; t_(Ret)=1.44 min; method LCMSBAS1) is obtained.

Quinazoline III-1 (Table 26):

MS (M + H)⁺; HPLC # Structure t_(Ret.) HPLC [min] method III-1

M + H = 509; t_(Ret.) = 1.44 LCMSBAS1

The following Examples describe the biological activity of the compounds according to the invention, without restricting the invention to these Examples.

Compounds of general formula (1) are characterised by their many possible applications in the therapeutic field. Particular mention should be made of those applications in which the inhibition of specific signal enzymes, particularly the inhibiting effect on the proliferation of cultivated human tumour cells but also on the proliferation of other cells such as endothelial cells, for example, are involved.

The activity of the compounds according to the invention on the kinase PDK1 which inhibits the signal transduction pathway is determined in an in vitro kinase assay with recombinantly prepared protein:

PDK1 Kinase Assay

Recombinant human PDK1 enzyme (aa 52-556) linked at its N-terminal end to His₆ is isolated from baculovirus-infected insect cells. Purified enzyme may be obtained for example from the University of Dundee, Scotland. The following components are combined in a well of a 96-well round-based dish (Greiner bio-one, No. 650101):

-   -   15 μL of compound to be tested in varying concentrations (e.g.         starting at 10 μM, and diluted in steps of 1:5) in APT buffer         (50 mM Tris/Cl pH 7.5; 0.05% β-mercaptoethanol; 10 mM         Mg-acetate; 0.0166% Tween 20; 3.33% DMSO)     -   15 μL His₆-PDK1 (aa 52-556) 3.33 ng/well) and PDKtide         (KTFCGTPEYLAPEVRRE PRILSEEEQEMFRDFDYIADWC), synthesised by         Pepceuticals Limited, Nottingham, United Kingdom; 25 μM final         concentration); His₆-PDK1 and PDKtide are together diluted         accordingly in assay buffer (50 mM tris pH 7.5, 0.05%         β-mercaptoethanol, 10 mM Mg-acetate); PDKtide is present in this         mixture as an 83.3 μM solution. These 30 μl are routinely         incubated for 30 min at RT.     -   20 μL ATP solution (25 μM ATP with 1.0 μCi/well gamma-P33-ATP).         The final concentration of Tween 20 is 0.005%.

The reaction is started by adding the ATP solution and the mixture is incubated for 90 min at RT. At the start of the reaction the dishes are shaken gently. The reaction is stopped by the addition of 50 μL/well of 500 mM phosphoric acid (H₃PO₄) and incubated for about 20 min at RT. The precipitate is transferred by harvesting onto filter plates (96-well microtitre filter plate: UniFilter GF/C; Perkin Elmer; No. 6005174), then washed 6 times with 50 mM H₃PO₄ and dried at 60° C. Then the plate is stuck down with sealing tape, 25 μL/well of scintillation solution (Microscint 0; Perkin Elmer; No. 6013611) are added and the amount of P33 precipitated is measured using the Wallac Betacounter. The measured data are evaluated using Graphpad Prism software.

Table 27 shows the IC₅₀ values of the example compounds of types I and II determined using the above assay.

TABLE 27 # PDK1 IC₅₀ [nM] I-1 103 I-2 37 I-3 8 I-4 311 I-5 229 I-6 68 I-7 94 I-8 103 I-9 3 I-10 11 I-11 88 I-12 35 I-13 34 I-14 27 I-15 68 I-16 33 I-17 95 I-18 17 I-19 4 I-20 4 I-21 149 I-22 6 I-23 8 I-24 117 I-25 42 I-26 588 I-27 3 I-28 21 I-29 41 I-30 2 I-31 5 I-32 8 I-33 40 I-34 3 I-35 21 I-36 87 I-37 5 I-38 56 I-39 21 I-40 2 I-41 3 I-42 3 I-43 5 I-44 11 I-45 8 I-46 7 I-47 4 I-48 3 I-49 9 I-50 1 I-51 2 I-52 4 I-53 8 I-54 8 I-55 4 I-56 3 I-57 9 I-58 8 I-59 5 I-60 7 I-61 2 I-62 2 I-63 4 I-64 5 I-65 7 I-66 654 I-67 940 I-68 233 I-69 64 I-70 1 I-71 4 I-72 2 I-73 4 I-74 8 I-75 1 I-76 2 I-77 4 I-78 9 I-79 80 I-80 132 I-81 66 I-82 119 I-83 62 I-84 21 I-85 185 I-86 86 I-87 23 I-88 15 I-89 23 I-90 110 I-91 38 I-92 128 I-93 12 I-94 55 I-95 33 I-96 74 I-97 38 I-98 25 I-99 36 I-100 14 I-101 5 I-102 13 I-103 33 I-104 71 I-105 47 I-106 119 I-107 212 I-108 116 I-109 166 I-110 137 I-111 29 I-112 71 I-113 15 I-114 23 I-115 780 I-116 1000 I-117 1000 I-118 853 I-119 554 I-120 656 I-121 156 I-122 3 I-123 2 I-124 2 I-125 2 I-125.1 3 I-125.2 5 I-125.3 5 I-125.4 12 I-125.5 16 I-125.6 26 I-125.7 32 I-125.8 46 I-125.9 2 I-125.10 3 I-125.11 4 I-125.12 6 I-125.13 6 I-125.14 60 I-125.15 11 I-125.16 11 I-125.17 2 I-125.18 2 I-125.19 3 I-125.20 17 I-125.21 2 I-125.22 3 I-125.23 4 I-126 86 I-127 98 I-128 116 II-1 12 II-2 171 II-3 134 II-4 26 II-5 16 II-6 98 II-7 105 II-8 91 II-9 443 II-10 229 II-11 135 II-12 161 II-13 184 II-14 158 II-15 445 II-16 218 II-17 488 II-18 41 II-19 500 II-20 13 II-21 515 II-22 371 II-23 142 II-24 77 II-25 126 II-26 199 II-27 52 II-28 110 II-29 156 II-30 21 II-31 114 II-32 124 II-33 79 II-34 59 II-35 59 II-36 468 II-37 44 II-38 97 II-39 137 II-40 74 II-41 61 II-42 697 II-43 8 II-44 40 II-45 63 II-46 6 II-47 117 II-48 15 II-49 50 II-50 182 II-51 770 II-52 6 II-53 486 II-54 8 II-55 60 II-56 6 II-57 357 II-58 10 II-59 9 II-60 8 II-61 57 II-62 16 II-63 14 I-64 57 II-65 58 II-66 98 II-67 96 II-68 20 II-69 21 II-70 185 II-71 1000 II-72 45 II-73 31 II-74 12 II-75 45 II-76 31 II-77 53 II-78 402 II-79 201 II-80 64 II-81 20 II-82 531 II-83 286 II-84 405 II-85 1000 II-86 355 II-87 24 II-88 19 II-89 35 II-90 86 II-91 14 II-92 56 II-93 24 II-94 27 II-95 544 II-96 607 II-97 1055 II-98 184 II-99 683 II-100 276 II-101 148 II-102 871 II-103 77 II-104 147 II-105 46 II-106 414

The antiproliferative activity of the compounds according to the invention is determined in the proliferation test on cultivated human tumour cells and/or in a cell cycle analysis, for example on PC-3 tumour cells:

Inhibition of Proliferation on Cultivated Human Tumour Cells (PC-3)

To measure proliferation on prostate carcinoma tumour cell line PC-3 (obtained from American Type Culture Collection (ATCC)) the cells are cultivated in Ham's F12K (Gibco) and 10% foetal calf serum (Gibco) and harvested in the log growth phase. Then the PC-3 cells are placed in 96-well plates (Costar) at a density of 2000 cells per well and incubated overnight in an incubator (at 37° C. and 5% CO₂), wherein on each plate 16 wells are used as controls [8 wells with cells to which only DMSO solution has been added (should yield 30-50% maximum value of reduced AlamarBlue), 4 wells containing only medium (medium control, after the addition of oxidised AlamarBlue reagent the background signal is obtained) and 4 wells where again only medium is added (after the addition of reduced AlamarBlue reagent it acts as a maximum value)]. The active substances are added to the cells in various concentrations (dissolved in DMSO; DMSO final concentration: 0.2%) (in each case as a double or triple measurement). After 5 d incubation 20 μl AlamarBlue reagent (Serotec) are added to each well, and the cells are incubated for a further 5-7 h. As a control, 20 μl reduced AlamarBlue reagent is added to each of 4 wells (AlamarBlue reagent which is autoclaved for 30 min). After incubation the colour change of the AlamarBlue reagent in the individual wells is determined in a SpectraMax Photometer (Molecular Devices) (extinction 530 nm, emission 590 nm, 5 s measuring time). The amount of AlamarBlue reagent reacted represents the metabolic activity of the cells. The relative cell activity is calculated in relation to the control (PC-3 cells without inhibitor) and the active substance concentration which inhibits the cell activity by 50% (EC₅₀) is derived. The values are calculated from the average of two or three individual measurements.

Many of the compounds according to the invention cause inhibition of proliferation by interfering with intracellular signal transduction pathways which are important for cell survival, predominantly, but not exclusively, in cells which have become dependent on these signal pathways during their development.

Compounds (1) according to the invention generally demonstrate good activity in cell assays of this kind, i.e. for example an EC₅₀ value in the PC-3 proliferation test of less than 10 μmol/L, often less than 5 μmol/L.

Biomarker Inhibition:

The substances of the present invention bring about cellular inhibition of PDK1-substrates. Examples of the latter are Phospho-Thr308/AKT, Phospho-Ser221,227/RSK, or phosphorylation sites on p70S6 kinase (Thr229). In order to determine the inhibitory effect, the cells are treated with substance for 2 h, for example, lysed and analysed by Western Blot and/or BioPlex analysis for phosphoproteins of this kind. Commercially obtainable phospho-specific antibodies to the above-mentioned phosphorylation sites are used.

In PC-3 or other signal pathway-mutated cell lines as a rule EC₅₀ values of less than 5 μmol/L, often less than 0.5 μmol/L, are achieved with the present compounds on these phosphorylation sites compared with the carrier control and after standardisation to the corresponding whole protein.

On the basis of their biological properties the compounds of general formula (1) according to the invention, their tautomers, racemates, enantiomers, diastereomers, mixtures thereof and the salts of all the above-mentioned forms are suitable for treating diseases characterised by excessive or abnormal cell proliferation or by aberrant activation of the phosphatidylinositol-3-kinase (PI3K)-PDK1-AKT signal pathway.

Such diseases include for example: viral infections (e.g. HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and/or parasitic infections; leukaemias, lymphomas and solid tumours (e.g. carcinomas and sarcomas), skin diseases (e.g. psoriasis); diseases based on hyperplasia which are characterised by an increase in the number of cells (e.g. fibroblasts, hepatocytes, bones and bone marrow cells, cartilage or smooth muscle cells or epithelial cells (e.g. endometrial hyperplasia)); bone diseases and cardiovascular diseases (e.g. restenosis and hypertrophy). They are also suitable for protecting proliferating cells (e.g. hair, intestinal, blood and progenitor cells) from DNA damage caused by radiation, UV treatment and/or cytostatic treatment.

For example, the following cancers may be treated with compounds according to the invention, without being restricted thereto: brain tumours such as for example acoustic neurinoma, astrocytomas such as pilocytic astrocytomas, fibrillary astrocytoma, protoplasmic astrocytoma, gemistocytary astrocytoma, anaplastic astrocytoma and glioblastoma, brain lymphomas, brain metastases, hypophyseal tumour such as prolactinoma, HGH (human growth hormone) producing tumour and ACTH producing tumour (adrenocorticotropic hormone), craniopharyngiomas, medulloblastomas, meningeomas and oligodendrogliomas; nerve tumours (neoplasms) such as for example tumours of the vegetative nervous system such as neuroblastoma sympathicum, ganglioneuroma, paraganglioma (pheochromocytoma, chromaffinoma) and glomus-caroticum tumour, tumours on the peripheral nervous system such as amputation neuroma, neurofibroma, neurinoma (neurilemmoma, Schwannoma) and malignant Schwannoma, as well as tumours of the central nervous system such as brain and bone marrow tumours; intestinal cancer such as for example carcinoma of the rectum, colon carcinoma, colorectal carcinoma, anal carcinoma, carcinoma of the large bowel, tumours of the small intestine and duodenum; eyelid tumours such as basalioma or basal cell carcinoma; pancreatic cancer or carcinoma of the pancreas; bladder cancer or carcinoma of the bladder; lung cancer (bronchial carcinoma) such as for example small-cell bronchial carcinomas (oat cell carcinomas) and non-small cell bronchial carcinomas (NSCLC) such as plate epithelial carcinomas, adenocarcinomas and large-cell bronchial carcinomas; breast cancer such as for example mammary carcinoma such as infiltrating ductal carcinoma, colloid carcinoma, lobular invasive carcinoma, tubular carcinoma, adenocystic carcinoma and papillary carcinoma; non-Hodgkin's lymphomas (NHL) such as for example Burkitt's lymphoma, low-malignancy non-Hodgkin's lymphomas (NHL) and mucosis fungoides; uterine cancer or endometrial carcinoma or corpus carcinoma; CUP syndrome (Cancer of Unknown Primary); ovarian cancer or ovarian carcinoma such as mucinous, endometrial or serous cancer; gall bladder cancer; bile duct cancer such as for example Klatskin tumour; testicular cancer such as for example seminomas and non-seminomas; lymphoma (lymphosarcoma) such as for example malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas (NHL) such as chronic lymphatic leukaemia, leukaemic reticuloendotheliosis, immunocytoma, plasmocytoma (multiple myeloma), immunoblastoma, Burkitt's lymphoma, T-zone mycosis fungoides, large-cell anaplastic lymphoblastoma and lymphoblastoma; laryngeal cancer such as for example tumours of the vocal cords, supraglottal, glottal and subglottal laryngeal tumours; bone cancer such as for example osteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma, osteoma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, giant cell tumour, chondrosarcoma, osteosarcoma, Ewing's sarcoma, reticulo-sarcoma, plasmocytoma, fibrous dysplasia, juvenile bone cysts and aneurysmatic bone cysts; head and neck tumours such as for example tumours of the lips, tongue, floor of the mouth, oral cavity, gums, palate, salivary glands, throat, nasal cavity, paranasal sinuses, larynx and middle ear; liver cancer such as for example liver cell carcinoma or hepatocellular carcinoma (HCC); leukaemias, such as for example acute leukaemias such as acute lymphatic/lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML); chronic leukaemias such as chronic lymphatic leukaemia (CLL), chronic myeloid leukaemia (CML); stomach cancer or gastric carcinoma such as for example papillary, tubular and mucinous adenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma, small-cell carcinoma and undifferentiated carcinoma; melanomas such as for example superficially spreading, nodular, lentigo-maligna and acral-lentiginous melanoma; renal cancer such as for example kidney cell carcinoma or hypernephroma or Grawitz's tumour; oesophageal cancer or carcinoma of the oesophagus; penile cancer; prostate cancer; throat cancer or carcinomas of the pharynx such as for example nasopharynx carcinomas, oropharynx carcinomas and hypopharynx carcinomas; retinoblastoma; vaginal cancer or vaginal carcinoma; plate epithelial carcinomas, adenocarcinomas, in situ carcinomas, malignant melanomas and sarcomas; thyroid carcinomas such as for example papillary, follicular and medullary thyroid carcinoma, as well as anaplastic carcinomas; spinalioma, epidormoid carcinoma and plate epithelial carcinoma of the skin; thymomas, cancer of the urethra and cancer of the vulva.

The new compounds may be used for the prevention, short-term or long-term treatment of the above-mentioned diseases, optionally also in combination with radiotherapy or other “state-of-the-art” compounds, such as e.g. cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids or antibodies.

The compounds of general formula (1) may be used on their own or in combination with other active substances according to the invention, optionally also in combination with other pharmacologically active substances.

Chemotherapeutic agents which may be administered in combination with the compounds according to the invention, include, without being restricted thereto, hormones, hormone analogues and antihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (e.g. goserelin acetate, luprolide), inhibitors of growth factors (growth factors such as for example “platelet derived growth factor” and “hepatocyte growth factor”, inhibitors are for example “growth factor” antibodies, “growth factor receptor” antibodies and tyrosine kinase inhibitors, such as for example cetuximab, gefitinib, imatinib, lapatinib and trastuzumab); antimetabolites (e.g. antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5-fluorouracil, capecitabin and gemcitabin, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine, fludarabine); antitumour antibiotics (e.g. anthracyclins such as doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g. cisplatin, oxaliplatin, carboplatin); alkylation agents (e.g. estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as for example carmustin and lomustin, thiotepa); antimitotic agents (e.g. Vinca alkaloids such as for example vinblastine, vindesin, vinorelbin and vincristine; and taxanes such as paclitaxel, docetaxel); topoisomerase inhibitors (e.g. epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantron) and various chemotherapeutic agents such as amifostin, anagrelid, clodronat, filgrastin, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer.

Other possible combination partners are 2-chlorodesoxyadenosine, 2-fluorodesoxycytidine, 2-methoxyoestradiol, 2C4,3-alethine, 131-I-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B, A 105972, A 204197, aldesleukin, alitretinoin, altretamine, alvocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine, aranose, arglabin, arzoxifene, atamestane, atrasentan, auristatin PE, AVLB, AZ10992, ABX-EGF, ARRY-300, ARRY-142886/AZD-6244, ARRY-704/AZD-8330, AS-703026, azacytidine, azaepothilone B, azonafide, BAY-43-9006, BBR-3464, BBR-3576, bevacizumab, biricodar dicitrate, BCX-1777, bleocin, BLP-25, BMS-184476, BMS-247550, BMS-188797, BMS-275291, BNP-1350, BNP-7787, BIBW 2992, BIBF 1120, bleomycinic acid, bleomycin A, bleomycin B, bryostatin-1, bortezomib, brostallicin, busulphan, CA-4 prodrug, CA-4, CapCell, calcitriol, canertinib, canfosfamide, capecitabine, carboxyphthalatoplatin, CCI-779, CEP-701, CEP-751, CBT-1 cefixime, ceflatonin, ceftriaxone, celecoxib, celmoleukin, cemadotin, CH4987655/RO-4987655, chlorotrianisene, cilengitide, ciclosporin, CDA-II, CDC-394, CKD-602, clofarabin, colchicin, combretastatin A4, CHS-828, CLL-Thera, CMT-3 cryptophycin 52, CTP-37, CP-461, CV-247, cyanomorpholinodoxorubicin, cytarabine, D 24851, decitabine, deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide, desoxyepothilone B, dexamethasone, dexrazoxanet, diethylstilbestrol, diflomotecan, didox, DMDC, dolastatin 10, doranidazole, E7010, E-6201, edatrexat, edotreotide, efaproxiral, eflornithine, EKB-569, EKB-509, elsamitrucin, epothilone B, epratuzumab, ER-86526, erlotinib, ET-18-OCH3, ethynylcytidine, ethynyloestradiol, exatecan, exatecan mesylate, exemestane, exisulind, fenretinide, floxuridine, folic acid, FOLFOX, FOLFIRI, formestane, galarubicin, gallium maltolate, gefinitib, gemtuzumab, gimatecan, glufosfamide, GCS-IOO, G17DT immunogen, GMK, GPX-100, GSK-5126766, GSK-1120212, GW2016, granisetron, hexamethylmelamine, histamine, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibritumomab, idatrexate, idenestrol, IDN-5109, IMC-1C11, immunol, indisulam, interferon alpha-2a, interferon alpha-2b, interleukin-2, ionafarnib, iproplatin, irofulven, isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2, JSF-154, J-107088, conjugated oestrogens, kahalid F, ketoconazole, KW-2170, lobaplatin, leflunomide, lenograstim, leuprolide, leuporelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin, lometrexol, losoxantrone, LU 223651, lurtotecan, mafosfamide, marimastat, mechloroethamine, methyltestosteron, methylprednisolone, MEN-10755, MDX-H210, MDX-447, MGV, midostaurin, minodronic acid, mitomycin, mivobulin, MK-2206, MLN518, motexafin gadolinium, MS-209, MS-275, MX6, neridronate, neovastat, nimesulide, nitroglycerin, nolatrexed, norelin, N-acetylcysteine, 06-benzylguanine, omeprazole, oncophage, ormiplatin, ortataxel, oxantrazole, oestrogen, patupilone, pegfilgrastim, PCK-3145, pegfilgrastim, PBI-1402, PEG-paclitaxel, PEP-005, P-04, PKC412, P54, PI-88, pelitinib, pemetrexed, pentrix, perifosine, perillylalcohol, PG-TXL, PG2, PLX-4032/RO-5185426, PT-100, picoplatin, pivaloyloxymethylbutyrate, pixantrone, phenoxodiol O, PKI166, plevitrexed, plicamycin, polyprenic acid, porfiromycin, prednisone, prednisolone, quinamed, quinupristin, RAF-265, ramosetron, ranpirnase, RDEA-119/BAY 869766, rebeccamycin analogues, revimid, RG-7167, rhizoxin, rhu-MAb, risedronate, rituximab, rofecoxib, Ro-31-7453, RO-5126766, RPR 109881 A, rubidazone, rubitecan, R-flurbiprofen, S-9788, sabarubicin, SAHA, sargramostim, satraplatin, SB 408075, SU5416, SU6668, SDX-101, semustin, seocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747, SRL-172, sorafenib, spiroplatin, squalamine, suberanilohydroxamic acid, sutent, T 900607, T 138067, TAS-103, tacedinaline, talaporfin, tariquitar, taxotere, taxoprexin, tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate, tesmilifene, tetraplatin, tetrodotoxin, tezacitabine, thalidomide, theralux, therarubicin, thymectacin, tiazofurin, tipifarnib, tirapazamine, tocladesine, tomudex, toremofin, trabectedin, TransMID-107, transretinic acid, traszutumab, tretinoin, triacetyluridine, triapine, trimetrexate, TLK-286TXD 258, urocidin, valrubicin, vatalanib, vincristine, vinflunine, virulizin, WX-UK1, vectibix, xeloda, XELOX, XL-281, XL-518/R-7420, YM-511, YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZDI839, zoledronat and zosuquidar.

Suitable preparations include for example tablets, capsules, suppositories, solutions-particularly solutions for injection (s.c., i.v., i.m.) and infusion—elixirs, emulsions or dispersible powders. The content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below. The doses specified may, if necessary, be given several times a day.

Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.

Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.

Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.

Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

The preparations are administered by the usual methods, preferably by oral or transdermal route, most preferably by oral route. For oral administration the tablets may, of course contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.

For parenteral use, solutions of the active substances with suitable liquid carriers may be used.

The dosage for intravenous use is from 1-1000 mg per hour, preferably between 5 and 500 mg per hour.

However, it may sometimes be necessary to depart from the amounts specified, depending on the body weight, the route of administration, the individual response to the drug, the nature of its formulation and the time or interval over which the drug is administered. Thus, in some cases it may be sufficient to use less than the minimum dose given above, whereas in other cases the upper limit may have to be exceeded. When administering large amounts it may be advisable to divide them up into a number of smaller doses spread over the day.

The formulation examples which follow illustrate the present invention without restricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet active substance according to formula (1) 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone  15 mg magnesium stearate  5 mg 500 mg

The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.

B) Tablets per tablet active substance according to formula (1)  80 mg lactose  55 mg corn starch 190 mg microcrystalline cellulose  35 mg polyvinylpyrrolidone  15 mg sodium-carboxymethyl starch  23 mg magnesium stearate  2 mg 400 mg

The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.

C) Ampoule solution active substance according to formula (1) 50 mg sodium chloride 50 mg water for inj.  5 mL

The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance. 

1. A compound of general formula (1)

wherein Q^(a) is a ring system optionally substituted by one or more identical or different R^(a) and/or R^(b), selected from among C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; R¹ and R² are selected independently of one another from among hydrogen, halogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄haloalkyl, —NH₂, —CN, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)₂, —OH, —OC₁₋₄alkyl, HO—C₁₋₄alkylene-, C₁₋₄alkyl-O—C₁₋₄alkylene-, H₂N—C₁₋₄alkylene-, —OC₁₋₄haloalkyl, (C₁₋₄alkyl)NH—C₁₋₄alkylene- and (C₁₋₄alkyl)₂N—C₁₋₄alkylene, while alkyl, alkenyl, alkynyl and alkylene mentioned in the above groups may optionally be substituted by one or more identical or different halogens; the ring system Q^(b) is selected from among

each R³ is independently selected from among halogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄haloalkyl, —NH₂, —CN, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)₂, —OH, —OC₁₋₄alkyl, HO—C₁₋₄alkylene-, HO—C₂₋₄alkylene-O—, C₁₋₄alkyl-O—C₁₋₄alkylene-, C₁₋₄haloalkyl-O—C₁₋₄alkylene-, H₂N—C₁₋₄alkylene-, C₁₋₄alkyl-O—C₂₋₄alkylene-O—, (C₁₋₄alkyl)NH—C₁₋₄alkylene-, (C₁₋₄alkyl)₂N—C₁₋₄alkylene-, —OC₁₋₄haloalkyl, H₂N—C₂₋₄alkylene-O—, —NH(C₂₋₄alkylene-NH₂), —NH[C₂₋₄alkylene-NH(C₁₋₄alkyl)], —NH[C₂₋₄alkylene-N(C₁₋₄alkyl)₂], (C₁₋₄alkyl)₂N—C₂₋₄alkylene-O—, (C₁₋₄haloalkyl)₂N—C₂₋₄alkylene-O—, (C₁₋₄haloalkyl)NH—C₂₋₄alkylene-O— and (C₁₋₄alkyl)NH—C₂₋₄alkylene-O—; n denotes the number 0, 1, 2 or 3 if Q^(b) corresponds to the ring system Q^(b)-4; each n independently denotes the number 0, 1 or 2 if Q^(b) corresponds to one of the ring systems Q^(b)-1, Q^(b)-2, Q^(b)-3 or Q^(b)-5; while a group R³ in the ring systems Q^(b)-1 to Q^(b)-5 in each case replaces a hydrogen; R⁴ denotes hydrogen or C₁₋₄alkyl; L denotes the group

and in the latter case the groups —CR⁵R⁶— and Q^(H) may assume both a cis and a trans configuration with respect to the double bond; R⁵ and R⁶ are each independently of one another selected from among hydrogen, halogen, C₁₋₄alkyl, C₁₋₄haloalkyl; the ring system Q^(H) is selected from among

R⁷ and R⁹ are each independently of one another selected from among hydrogen, halogen, —NR^(a)R^(a), —N(OR^(a))R^(a), —OR^(a), —COOR^(a), —COR^(a), —CONR^(a)R^(a), —SR^(a), —NO₂ and —CN or denote a group optionally substituted by one or more identical or different R^(b) and/or R^(c), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; R⁸ is independently selected from among hydrogen, —NR^(a)R^(a), —N(OR^(a))R^(a), —OR^(a), —COOR^(a), —COR^(a), —CONR^(a)R^(a) and —SR^(a) or denotes optionally substituted by one or more identical or different R^(b) and/or R^(c), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; R¹⁰ is independently selected from among —NR^(a)R^(a), —N(OR^(a))R^(a), —OR^(a) and —SR^(a) or a group optionally substituted by one or more identical or different R^(b) and/or R^(c), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R¹¹ and R¹² is independently selected from among R^(a) and R^(b); m denotes the number 0, 1 or 2; each R^(a) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(b) and/or R^(c), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(b) is independently selected from among —OR^(c), —NR^(c)R^(c), halogen, —CN, —NO₂, —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(c), —S(O)₂R^(c), —S(O)₂NR^(c)R^(c), —NHC(O)R^(c) and —N(C₁₋₄alkyl)C(O)R^(c) as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(c) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d) and/or R^(e), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(d) is independently selected from among —OR^(e), —NR^(e)R^(e), halogen, —CN, —NO₂, —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(e)R^(e), —S(O)₂R^(e), —S(O)₂NR^(e)R^(e), —NHC(O)R^(e) and —N(C₁₋₄alkyl)C(O)R^(e), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems; each R^(e) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(f) and/or R^(g), selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(f) is independently selected from among —OR^(g), —NR^(g)R^(g), halogen, —CN, —NO₂, —C(O)R^(g), —C(O)OR^(g), —C(O)NR^(g)R^(g), —S(O)₂R^(g), —S(O)₂NR^(g)R^(g), —NHC(O)R^(g) and —N(C₁₋₄alkyl)C(O)R^(g), as well as the bivalent substituent ═O, while the latter may only be a substituent in non-aromatic ring systems and each R^(g) is independently selected from among hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; or a salt thereof.
 2. The compound according to claim 1, wherein Q^(a) is a ring system optionally substituted by one or more identical or different R^(a) and/or R^(b) selected from among C₅₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl and 5-7 membered heterocyclyl, and R^(a) and R^(b) are defined as in claim
 1. 3. The compound according to claim 1 wherein the ring system Q^(H) is selected from among

R⁷ is independently selected from among hydrogen, —NR^(a)R^(a), —N(OR^(a))R^(a), —OR^(a), —COOR^(a), —COR^(a), —CONR^(a)R^(a) and —SR^(a), or denotes optionally substituted by one or more identical or different R^(b) and/or R^(c) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, and R¹¹, R¹², R^(a), R^(b), R^(c) and m are defined as in claim
 1. 4. The compound according to claim 3, wherein the ring system Q^(H) is selected from among

R⁷ is independently selected from among hydrogen, —NR^(a1)R^(a1), —N(OR^(a1))R^(a1), —OR^(a1), —COOR^(a1), —COR^(a1), —CONR^(a1)R^(a1) and —SR^(a1), or denotes optionally substituted by one or more identical or different R^(b1) and/or R^(c1) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(a1) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(b1) and/or R^(c1) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-14 membered heterocyclyl; each R^(b1) is independently selected from among —OR^(c1), —NR^(c1)R^(c1) and halogen; each R^(c1) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d1) and/or R^(e1) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-14 membered heterocyclyl; each R^(d1) is independently selected from among —OR^(e1), —CN and —C(O)OR^(e1); and each R^(e1) independently denotes hydrogen or a group optionally substituted by one or more identical or different C₃₋₆cycloalkyl selected from among C₁₋₆alkyl and C₃₋₁₀cycloalkyl.
 5. The compound according to claim 1, wherein the ring system Q^(H) is selected from among

R⁹ is independently selected from among hydrogen, —NR^(a)R^(a), —N(OR^(a))R^(a), —OR^(a), —COOR^(a), —COR^(a), —CONR^(a)R^(a) and —SR^(a), or a group optionally substituted by one or more identical or different R^(b) and/or R^(c) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, and R¹¹, R¹², R^(a), R^(b), R^(c) and m are defined as in claim
 1. 6. The compound according to claim 5, wherein the ring system Q^(H) is selected from among

R⁹ is independently selected from among hydrogen, —NR^(a2)R^(a2), —N(OR^(a2))R^(a2), —OR^(a2), —COOR^(a2), —COR^(a2), —CONR^(a2)R^(a2) and —SR^(a2), or denotes a group optionally substituted by one or more identical or different R^(b2) and/or R^(c2) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(a2) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(b2) and/or R^(c2) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-14 membered heterocyclyl; each R^(b2) is independently selected from among —OR^(c2), —NR^(c2)R^(c2) and halogen; each R^(c2) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d2) and/or R^(e2) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-14 membered heterocyclyl; each R^(d2) is independently selected from among —OR^(e2), —CN and —C(O)OR^(e2); and each R^(e2) independently denotes hydrogen or a group optionally substituted by one or more identical or different C₃₋₆cycloalkyl selected from among C₁₋₆alkyl and C₃₋₁₀cycloalkyl.
 7. The compound according to claim 6, wherein the ring system Q^(H) denotes

R⁹ is selected from among hydrogen, —NR^(a2)R^(a2), —OR^(a2) and —SR^(a2), or denotes a group optionally substituted by one or more identical or different R^(b2) and/or R^(c2) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, homomorpholinyl, azetidinyl and homopiperazinyl; each R^(a2) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(b2) and/or R^(c2) selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl and pyrrolidinyl; each R^(b2) is independently selected from among —OR^(c2), —NR^(c2)R^(c2) and halogen; each R^(c2) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d2) and/or R^(e2) selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl, pyrrolidinyl, morpholinyl, homomorpholinyl, piperazinyl, homopiperazinyl, oxetanyl and piperidinyl; each R^(d2) is independently selected from among —OR^(e2), —CN and —C(O)OR^(e2); and each R^(e2) independently denotes hydrogen or a group optionally substituted by one or more identical or different C₃₋₆cycloalkyl selected from among C₁₋₆alkyl and C₃₋₆cycloalkyl.
 8. The compound according to claim 1, wherein the ring system Q^(H) is selected from among

R⁸ is selected from among hydrogen, —NR^(a)R^(a), —N(OR^(a))R^(a), —OR^(a) and —SR^(a), or denotes a group optionally substituted by one or more identical or different R^(b) and/or R^(c) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; R⁹ is independently selected from among hydrogen, halogen, —NO₂, —CN and C₁₋₄alkyl, and R¹¹, R¹², R^(a), R^(b), R^(c) and m are defined as in claim
 1. 9. The compound according to claim 8, wherein the ring system Q^(H) is selected from among

R⁸ is selected from among —NR^(a3)R^(a3) and —OR^(a3), or denotes a group optionally substituted by one or more identical or different R^(b3) and/or R^(c3) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; R⁹ is independently selected from among hydrogen, halogen, —NO₂, —CN and C₁₋₄alkyl; each R^(a1) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(b3) and/or R^(c3) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl and 3-14 membered heterocyclyl; each R^(b3) is independently selected from among —OR^(c3) and —NR^(c3)R^(c3); and each R^(c3) independently denotes hydrogen or a group optionally substituted by one or more identical or different C₁₋₆alkyl selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl and 3-14 membered heterocyclyl.
 10. The compound according to claim 1, wherein the ring system Q^(H) is selected from among

R¹⁰ is independently selected from among —NR^(a)R^(a), —N(OR^(a))R^(a), —OR^(a) and —SR^(a) or denotes a group optionally substituted by one or more identical or different R^(b) and/or R^(c) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl, and R¹¹, R¹², R^(a), R^(b), R^(c) and m are defined as in claim
 1. 11. The compound according to claim 10, wherein the ring system Q^(H) is selected from among

R¹⁰ is independently selected from among —NR^(a4)R^(a4), —N(OR^(a4))R^(a4), —OR^(a4) and —SR^(a4) or denotes a group optionally substituted by one or more identical or different R^(b4) and/or R^(c4) selected from among C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(a4) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(b4) and/or R^(c4) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl and 3-14 membered heterocyclyl; each R^(b4) is independently selected from among —OR^(c4), —NR^(c4)R^(c4), —C(O)R^(c4), —C(O)OR^(c4), —C(O)NR^(c4)R^(c4), —NHC(O)R^(c4) and —N(C₁₋₄alkyl)C(O)R^(c4); each R^(c4) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(d4) and/or R^(e4) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-12 membered heteroaryl and 3-14 membered heterocyclyl; each R^(d4) denotes —OR^(e1); each R^(e4) independently denotes hydrogen or a group optionally substituted by one or more identical or different R^(f4) selected from among C₁₋₆alkyl and C₆₋₁₀aryl; and each R^(f4) denotes halogen.
 12. A compound selected from the group consisting of: I-88 1-[(3,4-difluorophenyl)methyl]-N-[3-[4-[3-(dimethylamino)propoxy]quinolin-6-yl]prop-2-ynyl]-6-oxopyrimidine-5-carboxamide; I-101 1-[(3,4-difluorophenyl)methyl]-6-oxo-N-[3-[4-[(3S)-pyrrolidin-3-yl]oxyquinolin-6-yl]prop-2-ynyl]pyrimidine-5-carboxamide; I-125.9 N-[3-[4-[[(3R)-1-methylpyrrolidin-3-yl]methoxy]quinolin-6-yl]prop-2-ynyl]-2oxo-1-[(3,4,5-trifluorophenyl)methyl]pyridine-3-carboxamide; I-125.11 N-[3-[4-[[(3S)-1-methylpyrrolidin-3-yl]methoxy]quinolin-6-yl]prop-2-ynyl]-2oxo-1-[(1R)-1-(3,4,5-trifluorophenyl)ethyl]pyridine-3-carboxamide; I-125.15 1-[(1R)-1-(3,4-difluorophenyl)-2-hydroxyethyl]-N-[3-(4-ethoxyquinolin-6-yl)prop-2-ynyl]-2-oxopyridine-3-carboxamide; I-125.17 N-[3-[4-[[(3R)-1-methylpiperidin-3-yl]methoxy]quinolin-6-yl]prop-2-ynyl]-2oxo-1-[(3,4,5-trifluorophenyl)methyl]pyridine-3-carboxamide; I-125.20 N-[3-[4-[[(3S)-1-(2-morpholin-4-ylethyl)piperidin-3-yl]methoxy]quinolin-6-yl]prop-2-ynyl]-2-oxo-1-[(1R)-1-(3,4,5-trifluorophenyl)ethyl]pyridine-3-carboxamide; I-125.22 1-[(3,4-difluorophenyl)methyl]-2-oxo-N-[3-[4-[[(3R)-1-propan-2-ylpiperidin-3-yl]methoxy]quinolin-6-yl]prop-2-ynyl]pyridine-3-carboxamide; I-125.21 1-[(1R)-2-hydroxy-1-(3,4,5-trifluorophenyl)ethyl]-N-[3-[4-[[(3R)-1-methylpiperidin-3-yl]methoxy]quinolin-6-yl]prop-2-ynyl]-2-oxopyridine-3-carboxamide; I-125.19 N-[3-[4-[[(3S)-1-(2-morpholin-4-ylethyl)piperidin-3-yl]methoxy]quinolin-6-yl]prop-2-ynyl]-2-oxo-1-[(3,4,5-trifluorophenyl)methyl]pyridine-3-carboxamide; I-125.16 1-[(1S)-1-(3,4-difluorophenyl)-2-hydroxyethyl]-N-[3-[4-(oxan-4-ylmethoxy)quinolin-6-yl]prop-2-ynyl]-2-oxopyridine-3-carboxamide; II-59 2-[(3,4-difluorophenyl)methyl]-6-methoxy-N-[3-[4-(methylamino)quinazolin-6-yl]prop-2-ynyl]-3-oxopyridazine-4-carboxamide; I-93 1-[(3,4-difluorophenyl)methyl]-N-[3-[4-[3-(dimethylamino)propoxy]quinolin-6-yl]prop-2-ynyl]-2-oxopyridine-3-carboxamide; I-122 1-[(3,4-difluorophenyl)methyl]-6-oxo-N-[3-[4-(pyrrolidin-3-ylmethoxy)quinolin-6-yl]prop-2-ynyl]pyrimidine-5-carboxamide; I-125.4 1-[(1S)-1-(3,4-difluorophenyl)-2-hydroxyethyl]-2-oxo-N-[3-[4-(oxolan-3-ylmethoxy)quinolin-6-yl]prop-2-ynyl]pyridine-3-carboxamide; I-30 1-[(1R)-1-(3,4-difluorophenyl)ethyl]-N-[3-[3-[(1-methylpiperidin-4-yl)amino]quinoxalin-6-yl]prop-2-ynyl]-2-oxopyridine-3-carboxamide; I-40 1-[(3,4-difluorophenyl)methyl]-N-[3-[3-[(4-morpholin-4-ylcyclohexyl)amino]quinoxalin-6-yl]prop-2-ynyl]-6-oxopyrimidine-5-carboxamide; I-42 N-[3-[3-[[4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]amino]quinoxalin-6-yl]prop-2-ynyl]-1-[(3,4-difluorophenyl)methyl]-6-oxopyrimidine-5-carboxamide; I-46 1-[(3,4-difluorophenyl)methyl]-N-[3-[3-[(1-ethylpiperidin-4-yl)amino]quinoxalin-6-yl]prop-2-ynyl]-2-oxopyridine-3-carboxamide; I-51 1-[(1S)-1-(3,4-difluorophenyl)ethyl]-N-[3-[3-[(1-ethylpiperidin-4-yl)amino]quinoxalin-6-yl]prop-2-ynyl]-2-oxopyridine-3-carboxamide; I-52 1-[(1S)-1-(3,4-difluorophenyl)ethyl]-N-[3-[3-[[1-(2-methoxyethyl)piperidin-4-yl]amino]quinoxalin-6-yl]prop-2-ynyl]-2-oxopyridine-3-carboxamide; I-72 1-[(3,4-difluorophenyl)methyl]-N-[3-[3-[(1-ethylpiperidin-4-yl)amino]quinolin-6-yl]prop-2-ynyl]-2-oxopyridine-3-carboxamide; I-74 1-[(3,4-difluorophenyl)methyl]-N-[3-[3-[[1-(2-methoxyethyl)piperidin-4-yl]amino]quinolin-6-yl]prop-2-ynyl]-2-oxopyridine-3-carboxamide; I-75 1-[(1S)-1-(3,4-difluorophenyl)ethyl]-N-[3-[3-[(1-ethylpiperidin-4-yl)amino]quinolin-6-yl]prop-2-ynyl]-2-oxopyridine-3-carboxamide; I-78 1-[(1S)-1-(3,4-difluorophenyl)ethyl]-N-[3-[3-[[1-(2-methoxyethyl)piperidin-4-yl]amino]quinolin-6-yl]prop-2-ynyl]-2-oxopyridine-3-carboxamide; I-47 1-[(3,4-difluorophenyl)methyl]-N-[3-[3-[[(3S,4R)-1-ethyl-3-fluoropiperidin-4-yl]amino]quinoxalin-6-yl]prop-2-ynyl]-6-oxopyrimidine-5-carboxamide; I-48 1-[(1R)-1-(3,4-difluorophenyl)-2-hydroxyethyl]-N-[3-[3-[[1-(2-methoxyethyl)-piperidin-4-yl]amino]quinoxalin-6-yl]prop-2-ynyl]-2-oxopyridine-3-carboxamide; I-49 1-[(3,4-difluorophenyl)methyl]-N-[3-[3-[[1-(2-methoxyethyl)piperidin-4-yl]amino]quinoxalin-6-yl]prop-2-ynyl]-2-oxopyridine-3-carboxamide; I-53 2-[(3,4-difluorophenyl)methyl]-N-[3-[3-[[1-(2-methoxyethyl)piperidin-4-yl]amino]quinoxalin-6-yl]prop-2-ynyl]-3-oxopyridazine-4-carboxamide; I-57 1-[(3,4-difluorophenyl)methyl]-N-[3-[3-[[1-(oxetan-3-yl)piperidin-4-yl]amino]quinoxalin-6-yl]prop-2-ynyl]-2-oxopyridine-3-carboxamide; I-61 N-[3-[3-[[4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]amino]quinoxalin-6-yl]prop-2-ynyl]-1-[(1S)-1-(3-fluorophenyl)-2-hydroxyethyl]-2-oxopyridine-3-carboxamide; I-73 1-[(3,4-difluorophenyl)methyl]-N-[3-[3-[[1-(2-methoxyethyl)piperidin-4-yl]amino]quinolin-6-yl]prop-2-ynyl]-6-oxopyrimidine-5-carboxamide; I-77 1-[(1R)-1-(3,4-difluorophenyl)-2-hydroxyethyl]-N-[3-[3-[[1-(2-methoxyethyl)-piperidin-4-yl]amino]quinolin-6-yl]prop-2-ynyl]-2-oxopyridine-3-carboxamide; I-87 1-[(3,4-difluorophenyl)methyl]-6-oxo-N-[3-(3-piperidin-4-yloxyquinolin-6-yl)prop-2-ynyl]pyrimidine-5-carboxamide; and II-88 1-[(3,4-difluorophenyl)methyl]-6-oxo-N-[3-[4-(1H-pyrrol-3-yl)quinolin-6-yl]prop-2-ynyl]pyrimidine-5-carboxamide; and the pharmaceutically acceptable salts thereof.
 13. A method for the treatment and/or prevention of cancer, infections, inflammations and autoimmune diseases comprising administering a therapeutically effective amount of a compound of claim 1 to patient in need thereof.
 14. A pharmaceutical preparation containing as active substance one or more compounds of general formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof, optionally in combination with conventional excipients and/or carriers.
 15. A pharmaceutical preparation comprising a compound of general formula (1) according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one other cytostatic or cytotoxic active substance, different from formula (1). 